http://www.gponline.

com/Clinical/article/1059596/Clinical-Review-Type-1-diabetesmellitus/ Section 1: Epidemiology and aetiology Type-1 diabetes is a disease of pancreatic islet beta-cell destruction, caused by an autoimmune process in more than 95 per cent of cases. The clinical manifestation of type-1 diabetes mellitus is preceded by an asymptomatic prodromal period (months to years) during which time immune destruction progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections (mumps, rubella) are the most likely environmental triggers contributing to the aetiopathogenesis. The diabetes autoimmunity study in the young (DAISY), followed newborns from birth and found no evidence that bovine milk ingestion, enteroviral infection or vaccination contribute to an increased risk of diabetes. The 'hygiene hypothesis' states that a sterile environment for young infants predisposes to deficiencies in immunoregulation in later life leading to T-helper 2 (Th2) diseases (asthma) and Th1 diseases (type-1 diabetes).1 The HLA on chromosome 6 was the first locus shown to be associated with the disease and contributes to about half of the familial basis of type-1 diabetes.2 Two combinations of HLA genes, which are of particular importance, the DR4-DQ8 and DR3DQ2, are present in 90 per cent of children with type-1 diabetes. A third haplotype, DR15-DQ6, is found in less than one per cent of children with type-1 diabetes, compared with more than 20 per cent of the general population and is considered to be protective.2 The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the affected family member with type-1 diabetes. If one haplotype is shared, the risk is 6 per cent and if two are shared the risk is 12 to 25 per cent. The highest risk is for identical twins with a concordance rate of 25 to 50 per cent. Epidemiology According to Diabetes UK, there are 2.6 million people diagnosed with diabetes in the UK. Among adults, it is estimated that up to 10 per cent of people with diabetes have type-1 diabetes. The EURODIAB collaborative study, a registry involving 44 countries in Europe, indicates an annual rate of increase in incidence of 3 to 4 per cent, with a larger increase in some central and eastern European countries. The incidence of type-1 diabetes in the UK has doubled every 20 years since 1945.3 Half of patients are diagnosed under the age of 15 and 90 per cent are diagnosed by the age of 30 years. The peak age for diagnosis in the UK is 10-14 years but is becoming younger, with a steep rise in patients diagnosed before the age of five years.

Section 2: Making the diagnosis The symptoms and signs relate to hyperglycaemia and the effects on fluid and electrolyte imbalance. Typical symptoms of polyuria, polydipsia and weight loss tend to develop insidiously over a period of weeks. In very young children, nocturnal enuresis may signal the onset. When insulin deficiency is severe and acute, the patient may present with diabetic ketoacidosis (DKA), an acute metabolic complication of type-1 diabetes, where ketone bodies are produced instead of the usual metabolic substrate for energy production. Symptoms may include abdominal pain, nausea, vomiting and a change in mental status varying from slight drowsiness to profound lethargy and in severe cases, coma. Investigations Hyperglycaemia is present in all cases. In autoimmune diabetes the three principal autoantigens for diagnosis are glutamic acid decarboxylase (GAD 65), 43a protein tyrosine phosphatase-like molecule (IA-2A) and insulin (IAA). About 90 per cent of caucasian children will have at least one of these autoantibodies at diagnosis.4 Tests for these antibodies are often only requested by a specialist when there is uncertainty between a diagnosis of type-1 and type-2 diabetes. These patients and their first degree relatives are at increased risk of other autoimmune diseases. Detection of two or more autoantibodies in relatives of patients with type-1 diabetes has a positive predictive value of more than 90 per cent. Guidelines on diagnosis The following points summarise recommendations from the NICE guidelines on type-1 diabetes (CG15).5 If classical symptoms are present, confirm diagnosis by a single laboratory glucose measurement. If classical symptoms are not present then two separate glucose readings are needed. HbA1c measurement may support diagnosis. Where a patient appears to have type-2 diabetes, consider type-1 diabetes if ketonuria is detected, or weight loss is marked, or the patient does not have features of the metabolic syndrome or other contributing illness. Consider the possibility that apparent type-1 diabetes is not type-1 diabetes in younger people with obesity or with a family history of diabetes, especially if of non-white ethnicity. Do not routinely use measurement of specific autoantibodies or C-peptide to confirm the diagnosis of type-1 diabetes - consider their use to discriminate type-1 from type-2 diabetes. Section 3: Managing the condition Management should be individualised and regular review of the patient's individual care plan should be performed and modified according to changes in circumstances and medical findings. The following recommendations for a structured care plan are based on the NICE guidelines (CG15).5

Provide patients with diabetes education, including advice on nutrition, physical activity and smoking. Teach self monitoring and set targets, aiming where possible for preprandial glucose levels of 4-7mmol/L and postprandial levels of <9mmol/L, and an HbA1c of <7.5 per cent. Arterial risk factors Where significant arterial risk exists, aim for an HbA1c of <6.5 per cent. Do not use arterial risk tables, equations or engines for arterial risk factor surveillance and management. Assess urine albumin excretion. If the result is abnormal (>2.5mg/mmol for men, >3.5mg/mmol for women) confirm the result at a subsequent visit. In all patients with confirmed kidney damage (including those with microalbuminuria alone), start ACE inhibitors and titrate to full dose. Check the patient's lipid profile, aiming for total cholesterol of <4mmol/L and LDL <2mmol/L. Use statins as first-line therapy. If triglyceride levels are still raised despite optimal glucose control, consider fibrates. Intervention is required if BP is above 135/85mmHg, or above 130/80mmHg with abnormal albumin excretion rate or another feature of the metabolic syndrome. Complications Assess annually for neuropathy, retinopathy and nephropathy. Give advice regarding foot care and assess for complications.

Give advice regarding foot care and assess for complications (Photograph: SPL) Structured education programmes Two major studies, the diabetes prevention trial (DPT)6 and the European nicotinamide diabetes intervention trial (ENDIT)7 have shown that strategies to prevent type-1 diabetes have not been successful. Thus, for individuals with type-1 diabetes, life-long insulin replacement and monitoring of blood glucose levels are required.

Structured education programmes like 'dose adjustment for normal eating' (DAFNE)8 and the 'Dusseldorf diabetes treatment and teaching programme'9 have demonstrated substantial benefits in improving glycaemic control and quality of life while saving costs, without increasing the risk of severe hypoglycaemia. These two structured education programmes emphasise the importance of carbohydrate counting and insulin dose adjustment according to the carbohydrate meal content and glucose levels. Section 4: Prognosis When an optimal glucose level is achieved and maintained in patients with type-1 diabetes, the risk of new eye disease is reduced by 76 per cent, worsening of existing eye disease by 54 per cent, early kidney disease by 54 per cent, more serious kidney problems by 39 per cent and development of neuropathy by 60 per cent.10

Retina damage from diabetes (Photograph: SPL) Cardiovascular risk The diabetes control and complications trial (DCCT) showed there was no glucose threshold for the development of microvascular complications. When the DCCT ended in 1993, researchers continued to study more than 90 per cent of participants over the next 10 years. The follow-up study, called epidemiology of diabetes interventions and complications10 reported that the risk of any heart disease was reduced by 42 per cent in patients who had been in the intensive treatment group. Patients in the intensive treatment group also cut their risk of non-fatal heart attack, stroke, or death from cardiovascular causes by 57 per cent. According to the National service framework for diabetes standards document published in 2001, life expectancy is reduced on average by more than 20 years in patients with type-1 diabetes and up to 10 years in type-2 diabetes. Mortality rates are up to five times higher for patients with diabetes.

Section 5: Case study A 37-year-old female was admitted to hospital with sore throat and general malaise. She was diagnosed with type-1 diabetes 18 years ago. She had a significant history of poor attendance to specialist clinics and had not seen her family doctor for three years. There was no record of any previous diabetes-related hospital admissions. She had attended the eye clinic in the past for extensive laser treatment to both her eyes. Kidney function She was on a basal bolus regimen and on admission she was not in DKA. Her HbA1c was 11 per cent and her creatinine was 849micromol/L with an eGFR value of 5ml/min. She had raised urine protein excretion of 8.49g per day. Vasculitic screen and ultrasound of kidneys were unremarkable. With fluid resuscitation over a period of one week her kidney function improved slightly (creatinine 514micromol/L and eGFR 8ml/min) and her urine output improved. She was transferred to a regional kidney unit for renal replacement therapy. Need for routine review This case highlights the debilitating and relentless nature of poorly controlled diabetes. A strong commitment to routine review by both the patient and the healthcare team should lead to prevention or delay of complications in many patients. This case highlights NICE's recommendation to establish diabetes registers to support recall systems for surveillance of complications and vascular risk. Section 6: Evidence base Clinical trials Intermediate-acting versus long-acting insulin for type-1 diabetes. A Cochrane review in 2008 analysed 23 RCTs where two insulin regimens were used for a period ranging from three months to one year.11 The weighted mean difference for the level of glycosylated haemoglobin was -0.08 (95 per cent confidence interval (CI) -0.12 to -0.04) in favour of the long acting insulin arm, but the observed difference was of doubtful clinical significance. Longer acting insulins were superior mostly in their nocturnal effect, which resulted in a lower level of fasting glucose levels and fewer episodes of nocturnal hypoglycaemia.

Insulin replacement therapy (Photograph: SPL) Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. A meta-analysis of 12 trials found that glycaemic control was better with CSII compared with multiple daily injections in patients who had severe hypoglycaemia, with a difference in HbA1c of 0.51 per cent.12 The study also reported a threefold reduction in severe hypoglycaemia with CSII compared with multiple daily injections. Another systematic review and meta-analysis of 20 studies reported that achieved HbA1c was significantly superior in the CSII group, the mean difference was -0.3 per cent (95 per cent CI 0.4 to -0.1, p=0.001) with significant reduction in the incidence of severe hypoglycemia.13 Thus, CSII is likely to be a clinically useful alternative for those patients in whom there is concern about severe hypoglycaemia. Guidelines NICE. Type-1 diabetes: diagnosis and management of type-1 diabetes in children, young people and adults. CG15. London, NICE, 2004.

Online Diabetes UK www.diabetes.org.uk This website provides useful links for both patients and healthcare professionals in the UK. American Diabetes Association www.diabetes.org Visit our GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum. CPD IMPACT: EARN MORE CREDITS These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

Hold a diabetes 'roadshow' for your local community. Screen for diabetes and hypertension, and talk about the risk factors for diabetes as well as complications and treatment. Hold a practice meeting to decide how to manage poorly attending patients with diabetes. Remind your team how to manage diabetic emergencies and ensure your doctor's bag has all the necessary equipment. Save this article and add notes with your free online CPD organiser at gponline.com/cpd Take clinical tests and claim certificates for CPD at myCME.com References 1. Gale E A. A missing link in the hygiene hypothesis? Diabetologia 2002; 45: 588-94. 2. Gillespie K. Type 1 Diabetes: Pathogenesis and Prevention. CMAJ 2006; 175(2). 3. Barnett T. The insulin treatment of Diabetes: A practical guide. EMAP Healthcare 1998. 4. Atkinson M A, Eisenbarth GS. Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Lancet 2001; 358: 221-9. 5. NICE. Type 1 diabetes in children, young people and adults. CG15, London, NICE, 2010. 6. Diabetes prevention trial-type 1 diabetes study group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002; 346(22): 1,685-9. 7. ENDIT. Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial. Diabetologia 2003; 46(3): 339-46. 8. DAFNE. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes. BMJ 2002; 325: 746. 9. Aschner P, Horton E, Leiter L A, et al. Practical steps to improving the management of type 1 diabetes. Int J Clin Pract 2010; 64(3): 305-15. 10. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med 2005; 353: 2,643-53. 11. Vardi M, Jacobson E, Nini A, et al. Intermediate acting versus long acting insulin for type 1 diabetes mellitus. Cochrane Database Syst Rev 2008; 3. CD006297. 12. Pickup J C, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: metaanalysis of randomised controlled trials. BMJ 2002; 324: 705.

13. Misso M L, Egberts K J, Page M, et al. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database Syst Rev 2010, Issue 1. CD005103.

http://en.wikipedia.org/wiki/Diabetes_mellitus_type_1 Diabetes mellitus type 1 (type 1 diabetes, T1DM, formerly insulin dependent or juvenile diabetes) is a form [2] of diabetes mellitus that results fromautoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose. The classical symptoms are polyuria (frequent [3] urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss. Incidence varies from 8 to 17 per 100,000 in Northern Europe and the U.S. with a high of about 35 per 100,000 in [4] Scandinavia to a low of 1 per 100,000 in Japan and China. Eventually, type 1 diabetes is fatal unless treated with insulin. Injection is the most common method of administering insulin although other methods are insulin pumps and inhaled insulin. Other alternatives are Pancreatic transplants that have been used and also pancreatic islet cell transplantation. Transplantation is experimental yet [5] growing. Most people who develop type 1 are otherwise healthy. understood, it is believed to be of immunological origin.
[6]

Although the cause of type 1 diabetes is still not fully

Type 1 can be distinguished from type 2 diabetes via a C-peptide assay, which measures endogenous insulin production. Type 1 treatment must be continued indefinitely in all cases. Treatment should not significantly impair normal activities but can be done adequately if sufficient patient training, awareness, appropriate care, discipline in testing and dosing of insulin is taken. However, treatment remains quite burdensome for many people. Complications may be associated with both low blood sugar and high blood sugar, both largely due to the nonphysiological manner in which insulin is replaced. Low blood sugar may lead to seizures or episodes of unconsciousness, and requires emergency treatment. High blood sugar may lead to increased fatigue and can also result in long-term damage to organs.
Contents
[hide]

1 Signs and symptoms 2 Cause

o o

2.1 Genetics 2.2 Environmental

3 Pathophysiology 4 Diagnosis

4.1 Autoantibodies

5 Prevention

o o

5.1 Immunosuppressive drugs 5.2 Diet

6 Management

o o

6.1 Insulin therapy 6.2 Pancreas transplantation

6.3 Islet cell transplantation

7 Complications

7.1 Driving

8 Epidemiology

8.1 Economics

9 Research

o o o

9.1 Foundations 9.2 GAD65 vaccine 9.3 T helper cell shift

10 Brittle diabetes 11 See also 12 References 13 External links

[edit]Signs

and symptoms

Overview of the most significant symptoms of diabetes

The classical symptoms of type 1 diabetes include: polyuria (frequent urination), polydipsia (increased [3] thirst), Xerostomia (dry mouth), polyphagia(increased hunger), fatigue, and weight loss. Before a person knows they have diabetes, blood sugar levels can be in a very high range for long periods of time which could cause diabetic ketoacidosis. These symptoms could be xeroderma (dry skin), rapid, deep breathing, [7] drowsiness, gastralgia(abdominal pain), and copremsis (vomiting). [edit]Cause Diabetes type 1 is induced by one or more of the following: genetic susceptibility, a diabetogenic trigger and/or [8] exposure to a driving antigen. [edit]Genetics

Type 1 diabetes is a polygenic disease, meaning many different genes contribute to its onset. Depending on locus or combination of loci, it can be dominant, recessive, or somewhere in between. The strongest gene, IDDM1, is located in the MHC Class II region on chromosome 6, at staining region 6p21. Certain variants of this gene increase the risk for decreased histocompatibility characteristic of type 1. Such variants include DRB1 0401, DRB1 0402, DRB1 0405, DQA 0301, DQB1 0302 and DQB1 0201, which are common in North Americans of European ancestry and in [9] [9] Europeans. Some variants also appear to be protective. The risk of a child developing type 1 diabetes is about 10% if the father has it, about 10% if a sibling has it, about 4% if the mother has type 1 diabetes and was aged 25 or younger when the child was born, and about 1% if the mother [10] was over 25 years old when the child was born. [edit]Environmental Environmental factors can influence expression of type 1. For identical twins, when one twin had type 1 diabetes, the other twin only had it 30%50% of the time. Despite having exactly the same genome, one twin had the disease, where the other did not; this suggests environmental factors, in addition to genetic factors, can influence disease [11] prevalence. Other indications of environmental influence include the presence of a 10-fold difference in occurrence among Caucasians living in different areas of Europe, and a tendency to acquire the incidence of the disease of the [8] destination country for people who migrate. [edit]Virus One theory, discussed by DeLisa Fairweather and Noel R. Rose, among others, proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the beta cells in the pancreas. The Coxsackie virus family or rubella is implicated, although the evidence is inconclusive. In type 1, pancreatic beta cells in the islets of Langerhans are destroyed, decreasing endogenous insulin production. This distinguishes type 1's origin from type 2. The type of diabetes a patient has is determined only by the cause fundamentally by whether the patient is insulin resistant (type 2) or insulin deficient without insulin resistance (type 1). This vulnerability is not shared by everyone, for not everyone infected by the suspected virus develops type 1 [13] diabetes. This has suggested presence of a genetic vulnerability and there is indeed an observed inherited tendency to develop type 1. It has been traced to particular HLA genotypes, though the connection between them and the triggering of an autoimmune reaction is still poorly understood. [edit]Diet Some researchers believe the autoimmune response is influenced by antibodies against cow's milk proteins. No connection has been established between autoantibodies, antibodies to cow's milk proteins, and type 1 diabetes. A subtype of type 1 (identifiable by the presence of antibodies against beta cells) typically develops slowly, so is often confused with type 2. In addition, a small proportion of type 2 cases manifest a genetic form of the disease [citation needed] called maturity onset diabetes of the young. Vitamin D in doses of 2000 IU per day given during the first year of a child's life has been connected in one study in northern Finland (where intrinsic production of Vitamin D is low due to low natural light levels) with an 80% reduction in the risk of getting type 1 diabetes later in life. The causal connection, if any, is obscure. Short breastfeeding period and short attendance at day care is associated with the risk of type 1 diabetes [15] in Czech children. [edit]Chemicals and drugs Some chemicals and drugs preferentially destroy pancreatic cells. Pyrinuron (Vacor, N-3-pyridylmethyl-N'-pnitrophenyl urea), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental or intentional ingestion. Vacor was withdrawn from the U.S. market in 1979, but is still used in some countries. Zanosar is the trade name for streptozotocin, an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer; it also kills beta cells, resulting in
[14] [12]

loss of insulin production. Other pancreatic problems, including trauma, pancreatitis or tumors (either malignant or benign), can also lead to loss of insulin production. [edit]Pathophysiology The pathophysiology in diabetes type 1 is basically a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present. Individual risk factors can have separate pathophysiological processes to, in turn, cause this beta cell destruction. Still, a process that appears to be common to most risk factors is anautoimmune response towards beta cells, involving an expansion of autoreactive CD4+ and CD8+ T helper cells, autoantibody-producing B cells and activation [9] of the innate immune system. [edit]Diagnosis See also: Glycosylated hemoglobin and Glucose tolerance test

Diabetes diagnostic criteria

[16][17]

edit

Condition

2 hour glucose

Fasting glucose

HbA1c

mmol/l(mg/dl)

mmol/l(mg/dl)

Normal

<7.8 (<140)

<6.1 (<110)

<6.0

Impaired fasting glycaemia

<7.8 (<140)

6.1(110) & <7.0(<126) 6.06.4

Impaired glucose tolerance

7.8 (140)

<7.0 (<126)

6.06.4

Diabetes mellitus

11.1 (200)

7.0 (126)

6.5

Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any [18] one of the following:

Fasting plasma glucose level at or above 7.0 mmol/L (126 mg/dL). Plasma glucose at or above 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in aglucose tolerance test. Symptoms of hyperglycemia and casual plasma glucose at or above 11.1 mmol/L (200 mg/dL). Glycated hemoglobin (hemoglobin A1C) at or above 6.5. (This criterion was recommended by theAmerican [19] Diabetes Association in 2010, although it has yet to be adopted by the WHO.)

About a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis (a type of metabolic acidosis which is caused by high concentrations of ketone bodies, formed by the breakdown of fatty acids

and the deamination of amino acids) by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening, detection of hyperglycemia during other medical investigations, and secondary symptoms such as vision changes or unexplainable fatigue. Diabetes is often detected when a person suffers a problem that may be caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia. A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the abovelisted methods on a different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to [20] complete and offers no prognostic advantage over the fasting test. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes mellitus. Patients with fasting glucose levels from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) are considered to have impaired fasting glucose. Patients with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL (11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus and [21] cardiovascular disease. [edit]Autoantibodies The appearance of diabetes-related autoantibodies has been shown to be able to predict the appearance of diabetes type 1 before any hyperglycemia arises, the main ones being islet cell autoantibodies, insulin autoantibodies, autoantibodies targeting the 65-kDa isoform of glutamic acid decarboxylase (GAD) and autoantibodies targeting [8] the phosphatase-related IA-2 molecule. By definition, the diagnosis of diabetes type 1 can be made first at the appearance of clinical symptoms and/or signs, but the emergence of autoantibodies may itself be termed "latent autoimmune diabetes". Not everyone with autoantibodies progresses to diabetes type 1, but the risk increases with the number of antibody types, with three to four antibody types giving a risk of progressing to diabetes type 1 of 60% [8] 100%. The time interval from emergence of autoantibodies to frank diabetes type 1 can be a few months in infants [8] and young children, but in some people it may take years in some cases more than 10 years. Islet cell autoantibodies are detected by conventional immunofluorescence, while the rest are measured with [8] specific radiobinding assays. [edit]Prevention Type 1 diabetes is not currently preventable. Some researchers believe it might be prevented at the latent [9] autoimmune stage, before it starts destroying beta cells. [edit]Immunosuppressive
[22]

drugs

Cyclosporine A, an immunosuppressive agent, has apparently halted destruction of beta cells (on the basis of [9] reduced insulin usage), but its nephrotoxicity and other side effects make it highly inappropriate for long-term use. Anti-CD3 antibodies, including teplizumab and otelixizumab, had suggested evidence of preserving insulin production [9] (as evidenced by sustained C-peptide production) in newly diagnosed type 1 diabetes patients. A probable mechanism of this effect was believed to be preservation of regulatory T cells that suppress activation of the immune [9] system and thereby maintain immune system homeostasis and tolerance to self-antigens. The duration of the effect [9] is still unknown, however. In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical [23][24] efficacy, potentially due to an insufficient dosing schedule. An anti-CD20 antibody, rituximab, inhibits B cells and has been shown to provoke C-peptide responses three months [9] after diagnosis of type 1 diabetes, but long-term effects of this have not been reported. [edit]Diet

Some research has suggested breastfeeding decreases the risk in later life; various other nutritional risk factors [27] are being studied, but no firm evidence has been found. Giving children 2000 IU of Vitamin D during their first year [28] of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure. Children with antibodies to beta cell proteins (i.e. at early stages of an immune reaction to them) but no overt diabetes, and treated with vitamin B3 (niacin), had less than half the diabetes onset incidence in a seven-year time span than did the general population, and an even lower incidence relative to those with antibodies as above, but [29] who received no vitamin B3. [edit]Management Further information: Diabetes management [edit]Insulin

[25][26]

therapy

Type 1 is treated with insulin replacement therapyeither via subcutaneous injection or insulin pump, along with attention to dietary management, typically including carbohydrate tracking, and careful monitoring of blood glucose levels using glucose meters. Today, the most common insulins are biosynthetic products produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even sometimes insulin from [30] fish. Major global suppliers include Eli Lilly and Company, Novo Nordisk, and Sanofi-Aventis. A more recent trend, from several suppliers, is insulin analogs which are slightly modified insulins with different onset or duration of action times. Untreated type 1 diabetes commonly leads to coma, often from diabetic ketoacidosis, which is fatal if untreated. Ketoacidosis causes cerebral edema (accumulation of liquid in the brain). This complication is very life-threatening; it [31] makes ketoacidosis the most common cause of death in pediatric diabetes. Continuous glucose monitors have been developed and marketed which can alert patients to the presence of dangerously high or low blood sugar levels, but technical limitations have limited the impact these devices have had on clinical practice so far. Treatment of diabetes focuses on lowering blood sugar or glucose (BG) to the near normal range, approximately 80 [32] 140 mg/dl (4.47.8 mmol/L). The ultimate goal of normalizing BG is to avoid long-term complications that affect the nervous system (e.g. peripheral neuropathy leading to pain and/or loss of feeling in the extremities), and the cardiovascular system (e.g. heart attacks, vision loss). People with type 1 diabetes always need to use insulin, but treatment can lead to low BG (hypoglycemia), i.e. BG less than 70 mg/dl (3.9 mmol/l). Hypoglycemia is a very common occurrence in people with diabetes, usually the result of a mismatch in the balance among insulin, food and physical activity, although the nonphysiological method of delivery also plays a role. [edit]Pancreas

transplantation

Main article: Pancreas transplantation In more extreme cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression required is considered by many physicians to be more dangerous than continued insulin replacement therapy, so is generally only used with or some time after a kidney transplant. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs such as cyclosporine. Nevertheless this allows the introduction of a new, functioning pancreas to a patient with diabetes without any additional immunosuppressive therapy. However, pancreas transplants alone can be wise in patients with [33] extremely labile type 1 diabetes mellitus. [edit]Islet

cell transplantation

Main article: Islet cell transplantation

Experimental replacement of beta cells (by transplant or from stem cells) is being investigated in several research programs. Islet cell transplantation is less invasive than a pancreas transplant, which is currently the most commonly used approach in humans. In one variant of this procedure, islet cells are injected into the patient's liver, where they take up residence and begin to produce insulin. The liver is expected to be the most reasonable choice because it is more accessible than the pancreas, and islet cells seem to produce insulin well in that environment. The patient's body, however, will treat the new cells just as it would any other introduction of foreign tissue, unless a method is developed to produce them from the patient's own stem cells or an identical twin is available who can donate stem cells. The immune system will attack the cells as it would a bacterial infection or a skin graft. Thus, patients now also need to undergo treatment involving immunosuppressants, which reduce immune system activity. Recent studies have shown islet cell transplants have progressed to the point where 58% of the patients in one study [34] were insulin-independent one year after transplantion. Scientists in New Zealand with Living Cell Technologies are currently in human trials with Diabecell, placing pig islets within a protective capsule derived of seaweed which enables insulin to flow out and nutrients to flow in, while protecting the islets from immune system attack via white blood cells. [edit]Complications Further information: Complications of diabetes mellitus Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, [35] [36] and diabetic retinopathy, among others. However, cardiovascular disease as well as neuropathy may have an autoimmune basis, as well. [edit]Driving Studies conducted in the United States and Europe showed that drivers with type 1 diabetes had twice as many collisions as their nondiabetic spouses, demonstrating the increased risk ofdriving collisions in the type 1 diabetes population. Diabetes can compromise driving safety in several ways. First, long-term complications of diabetes can interfere with the safe operation of a vehicle. For example, diabetic retinopathy (loss of peripheral vision or visual acuity), or peripheral neuropathy (loss of feeling in the feet) can impair a drivers ability to read street signs, control the speed of the vehicle, apply appropriate pressure to the brakes, etc. Second, hypoglycemia can affect a persons thinking processes, coordination, and state of consciousness. This [39][41] disruption in brain functioning, neuroglycopenia, can impair driving ability. A study involving people with type 1 diabetes found that individuals reporting two or more hypoglycemia-related driving mishaps differ physiologically and [42] behaviorally from their counterparts who report no such mishaps. For example, during hypoglycemia, drivers who had two or more mishaps reported fewer warning symptoms, their driving was more impaired, and their body released less epinephrine (a hormone that helps raise BG). Additionally, individuals with a history of hypoglycemia[43] related driving mishaps appear to use sugar at a faster rate and are relatively slower at processing [44] information. These findings indicate that although anyone with type 1 diabetes may be at some risk of experiencing disruptive hypoglycemia while driving, there is a subgroup of type 1 drivers who are more vulnerable to such events. Given the above research findings, drivers with type 1 diabetes and a history of driving mishaps are recommended to never drive when their BG is less than 70 mg/dl. Instead, these drivers are advised to treat hypoglycemia and delay [42] driving until their BG is above 90 mg/dl. Such drivers should also learn as much as possible about what causes their hypoglycemia, and use this information to avoid future hypoglycemia while driving. Studies funded by the National Institutes of Health (NIH) have demonstrated that face-to-face training programs designed to help individuals with type 1 diabetes better anticipate, detect, and prevent extreme BG can reduce the [45][46][47] occurrence of future hypoglycemia-related driving mishaps. An internet-version of this training has also been
[39][40] [37] [38]

shown to have significant beneficial results. Additional NIH funded research to develop internet interventions [49] specifically to help improve driving safety in drivers with type 1 diabetes is currently underway. [edit]Epidemiology Type 1 diabetes causes an estimated 510% of all diabetes cases or 1122 million worldwide. In 2006 it affected 440 thousand children under 14 years of age and was the primary cause of diabetes in those less than 10 [51] [51] years of age. The incidence of type 1 diabetes has been increasing by about 3% per year. Rates vary widely by country. In Finland, the incidence is a high of 35 per 100,000 per year, in Japan and China a low of 1 to 3 per 100,000 per year, and in Northern Europe and the U.S., an intermediate of 8 to 17 per 100,000 per [4][52] year. Type 1 diabetes was previously known as juvenile diabetes to distinguish it from type 2 diabetes, which generally has a later onset; however, the majority of new-onset type 1 diabetes is seen in adults. Studies using antibody testing (glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated autoantibodies) to distinguish between type 1 and type 2 diabetes demonstrate that most new-onset type 1 diabetes is seen in adults. Adult-onset type 1 autoimmune diabetes is two to three times more common than classic childhood-onset [53] autoimmune diabetes. [edit]Economics In the US in 2008, about one million people were diagnosed with type 1 diabetes. The disease was estimated to cause $10.5 billion in annual medical costs ($875 per month per diabetic) and an additional $4.4 billion in indirect [54] costs ($366 per month per diabetic). [edit]Research [edit]Foundations The Juvenile Diabetes Research Foundation funds type 1 diabetes research and has offices in the UK, Denmark, USA, Canada, Australia, Israel, Mexico and India. The Diabetes Research Institute Foundation was founded by a group of parents of children with diabetes and funds research for a cure for type 1 diabetes. The International Diabetes Federation is a worldwide alliance of over 160 countries to address diabetes research and treatment. The American Diabetes Association funds some type 1 research along with other a variety of diabetes-related research (not necessarily cure-specific), including type 2 diabetes, gestational diabetes and others) that looks at treatments and prevention, as well as some cure-specific research. Diabetes Australia is involved in promoting research and education in Australia on both type 1 and type 2 diabetes. The Canadian Diabetes Association is involved in educating, researching, and sustaining type 1 diabetes patients in Canada. Pacific Northwest Diabetes Research Institute conducts clinical and basic research on type 1 and type 2 diabetes. [edit]GAD65
[50] [22]

[48]

vaccine

Injections with a vaccine containing GAD65, an autoantigen involved in type 1 diabetes, has in clinical trials delayed [9] the destruction of beta cells when treated within six months of diagnosis. Patients treated with the substance [55] showed higher levels of regulatory cytokines, thought to protect the beta cells. Phase III trials are under way in the [56] [57][58][59] USA and in Europe. Two prevention studies, where the vaccine is given to persons who have not yet [60][61][62] developed diabetes are underway. [edit]T

helper cell shift

If a biochemical mechanism can be found to prevent the immune system from attacking beta cells, it may be administered to prevent commencement of diabetes type 1. Several groups are trying to achieve this by causing the activation state of the immune system to change from type 1 T helper cell (Th1) state ("attack" by killer T Cells) to Th2 state (development of new antibodies). This Th1-Th2 shift occurs via a change in the type of cytokine signaling

molecules being released by T-cells. Instead of proinflammatory cytokines, the T-cells begin to release cytokines that [63] inhibit inflammation. This phenomenon is commonly known as "acquired immune tolerance". [edit]Brittle

diabetes

Insulin-dependent diabetes characterized by dramatic and recurrent swings in glucose levels, often occurring for no apparent reason, is sometimes known as brittle diabetes, unstable diabetes or labile diabetes, although some experts [64] say the "brittle diabetes" concept "has no biologic basis and should not be used". The results of such swings can be irregular and unpredictablehyperglycemias, frequently involving ketosis, and sometimes serious hypoglycemias. [65] Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics. An insulin pump may be recommended for brittle diabetes to reduce the number of hypoglycemic episodes and better control the morning rise of blood sugar [66] due to the dawn phenomenon. In a small study, 10 of 20 brittle diabetic patients aged 18-23 years who could be traced had died within 22 years, and the remainder, though suffering high rates of complications, were no longer [67] brittle. These results were similar to those of an earlier study by the same authors which found a 19% mortality in [68] 26 patients after 10.5 years. Because brittle diabetes is defined as "episodes of hypoglycemia or hyperglycemia that, whatever their cause, [69] constantly disrupt a patient's life", it can have many causes, some of which include:

errors in diabetes management, which can include too much insulin being given. interactions with other medical conditions. psychological problems. biological factors that interfere with how insulin is processed within the body.

One of these biological factors is the production of insulin autoantibodies. High antibody titers can cause episodes of hyperglycemia by neutralizing the insulin, cause clinical insulin resistancerequiring doses of over 200 IU/day. However, antibodies may also fail to buffer the release of the injected insulin into the bloodstream after subcutaneous injection, resulting in episodes of hypoglycemia. In some cases, changing the type of insulin administered can resolve [69] this problem. There have been a number of reports that insulin autoantibodies can act as a "sink" for insulin and affect the time to peak, half-life, distribution space, and metabolic clearance, though in most patients these effects are [70] small.

http://emedicine.medscape.com/article/117739-medication#showall Background
Type 1 diabetes mellitus (DM) is a multisystem disease with both biochemical and anatomic/structural consequences. It is a chronic disease of carbohydrate, fat, and protein metabolism caused by the lack of insulin, which results from the marked and progressive inability of the pancreas to secrete insulin because of autoimmune destruction of the beta cells. (See Pathophysiology.) (See alsoGlucose Intolerance.) Type 1 DM can occur at any age. It is most common in juveniles but can also develop in adults, especially in those in their late 30s and early 40s. (See Epidemiology.) Unlike people with type 2 DM, those with type 1 DM usually are not obese and usually present initially with diabetic ketoacidosis (DKA). The distinguishing characteristic of a patient with type 1 DM is that if his or her insulin is withdrawn, ketosis and eventually ketoacidosis develop. Therefore, these patients are dependent on exogenous insulin. (See Presentation.) Treatment of type 1 DM requires lifelong insulin therapy. A multidisciplinary approach by the physician, nurse, and dietitian, with regular specialist consultation, is needed to control glycemia, as well as to limit the development of its devastating complications and manage such complications when they do occur. (See Treatmentand Medication.) Despite the differences between type 1 and type 2 DM, the costs of the 2 conditions are often combined. In a study that focused on type 1 alone, Tao et al estimated that in the United States, type 1 DM is responsible for $14.4 billion in medical costs and lost income each year.[1]

Pathophysiology
Type 1 DM is the culmination of lymphocytic infiltration and destruction of insulin-secreting beta cells of the islets of Langerhans in the pancreas. As beta-cell mass declines, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels. After 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes may be diagnosed. Patients need exogenous insulin to reverse this catabolic condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism. Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules. Approximately 85% of type 1 DM patients have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD), an enzyme found within pancreatic beta cells. The prevalence of type 1 DM is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease. Pilia et al found a higher prevalence of islet cell antibodies (IA2) and antiGAD antibodies in patients with autoimmune thyroiditis.[2] A study by Philippe et al used computed tomography (CT) scans, glucagon stimulation test results, and fecal elastase-1 measurements to confirm reduced pancreatic volume in individuals with DM.[3] This finding, which was equally present in both type 1 and type 2 DM, may also explain the associated exocrine dysfunction that occurs in DM. Polymorphisms of the class II human leukocyte antigen (HLA) genes that encode DR and DQ are the major genetic determinants of type 1 DM. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. Heterozygotes for those haplotypes are at significantly greater risk for DM than homozygotes. HLA-DQs are also considered specific markers of type 1 DM susceptibility. In contrast, some haplotypes (eg, HLA-DR2) confer strong protection against type 1 DM.[4]

Sensory and autonomic neuropathy

Sensory and autonomic neuropathy in people with diabetes are caused by axonal degeneration and segmental demyelination. Many factors are involved, including the accumulation of sorbitol in peripheral sensory nerves from sustained hyperglycemia. Motor neuropathy and cranial mononeuropathy result from vascular disease in blood vessels supplying nerves.

Angiopathy

Using nailfold video capillaroscopy, Barchetta et al detected a high prevalence of capillary changes in patients with diabetes, particularly those with retinal damage. This reflects a generalized microvessel involvement in both type 1 and type 2 DM.[5] Microvascular disease causes multiple pathologic complications in people with diabetes. Hyaline arteriosclerosis, a characteristic pattern of wall thickening of small arterioles and capillaries, is widespread and is responsible for ischemic changes in the kidney, retina, brain, and peripheral nerves. Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. It is a significant component of multiple renal lesions in diabetes. Vitamin D deficiency is an important independent predictor of development of coronary artery calcification in individuals with type 1 DM.[6] Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications.[7]

Nephropathy
In the kidneys, the characteristic wall thickening of small arterioles and capillaries leads to diabetic nephropathy, which is characterized by proteinuria, glomerular hyalinization (Kimmelstiel-Wilson), and chronic renal failure. Exacerbated expression of cytokines such as tumor growth factor beta 1 is part of the pathophysiology of glomerulosclerosis, which begins early in the course of diabetic nephropathy. Genetic factors influence the development of diabetic nephropathy. Single-nucleotide polymorphisms affecting the factors involved in its pathogenesis appear to influence the risk for diabetic nephropathy in different people with type 1 DM.[8]

Etiology
Type 1A DM results from autoimmune destruction of the beta cells of the pancreas and involves both genetic predisposition and an environmental component.

Genetic factors
Although the genetic aspect of type 1 DM is complex, with multiple genes involved, there is a high sibling relative risk.[9] Whereas dizygotic twins have a 5-6% concordance rate for type 1 DM,[10] monozygotic twins will share the diagnosis more than 50% of the time by the age of 40 years. [11] For the child of a parent with type 1 DM, the risk varies according to whether the mother or the father has diabetes. Children whose mother has type 1 DM have a 2-3% risk of developing the disease, whereas those whose father has the disease have a 5-6% risk. When both parents are diabetic, the risk rises to almost 30%. In addition, the risk for children of parents with type 1 DM is slightly higher if onset of the disease occurred before age 11 years and slightly lower if the onset occurred after the parents 11th birthday. The genetic contribution to type 1 DM is also reflected in the significant variance in the frequency of the disease among different ethnic populations. Type 1 DM is most prevalent in European populations, with people from northern Europe more often affected than those from Mediterranean regions.[12] The disease is least prevalent in East Asians.[13] Genome-wide association studies have identified several loci that are associated with type 1 DM, but few causal relations have been established. The genomic region most strongly associated with other autoimmune diseases, the major histocompatibility complex (MHC), is the location of several susceptibility loci for type 1 DMin particular, class II HLA DR and DQ haplotypes.[14, 15, 16] A hierarchy of DR-DQ haplotypes associated with increased risk for type 1 DM has been established. The most susceptible haplotypes are as follows[17] :

DRB1*0301 - DQA1*0501 - DQB1*0201 (odds ratio [OR] 3.64) DRB1*0405 - DQA1*0301 - DQB1*0302 (OR 11.37) DRB1*0401 - DQA1*0301 - DQB*0302 (OR 8.39) DRB1*0402 - DQA1*0301 - DQB1*0302 (OR 3.63) DRB1*0404 - DQA1*0301 - DQB1*0302 (OR 1.59) DRB1*0801 - DQB1*0401 - DQB1*0402 (OR 1.25) Other haplotypes appear to offer protection against type 1 DM. These include the following [17] : DRB1*1501 - DQA1*0102 - DQB1*0602 (OR 0.03)

DRB1*1401 - DQA1*0101 - DQB1*0503 (OR 0.02) DRB1*0701 - DQA1*0201 - DQB1*0303 (OR 0.02) From 90% to 95% of young children with type 1 DM carry HLA-DR3 DQB1*0201, HLA-DR4 DQB1*0302, or both. Carriage of both haplotypes (ie, DR3/4 heterozygotes) confers the highest susceptibility. These high-risk haplotypes are found primarily in people of European descent; other ethnic groups are less well studied. In African Americans, the DRB1*07:01 - DQA1*03:01 -DQB1*02:01g haplotype is associated with increased risk (OR 3.96), whereas the DRB1*07:01-DQA1*02:01 - DQB1*02:01g haplotype appears to be protective (OR 0.34).[18] The insulin gene (INS), which encodes for the pre-proinsulin peptide, is adjacent to a variable number of tandem repeats (VNTR) polymorphism at chromosome 11p15.5.[19] Different VNTR alleles may promote either resistance or susceptibility to type 1 DM through their effect on INS transcription in the thymus; for example, protective VNTRs are associated with higher INS expression, which may promote deletion of insulin-specific T cells.[20] Other genes that have been reported to be involved in the mechanism of type 1 DM include CTLA4 (important in Tcell activation), PTPN22 (produces LYP, a negative regulator of T-cell kinase signaling), and IL2RA (encodes for CD25 which is involved with regulating T-cell function). UBASH3A (also known as STS2), may be involved in the increased risk not only of type 1 DM but also of other autoimmune disease and Down syndrome; it is located on locus chromosome 21q22.3.[21] In addition, genome-wide association studies have implicated numerous other genes, including the following [22] :

SH2B3 ERBB3 CLEC16A IL18RAP PTPN2 CCR5

Environmental factors
Extragenetic factors also may contribute. Potential triggers for immunologically mediated destruction of the beta cells include viruses (eg, enterovirus,[23] mumps, rubella, and coxsackievirus B4), toxic chemicals, exposure to cows milk in infancy,[24] and cytotoxins. Combinations of factors may be involved. Lempainen et al found that signs of an enterovirus infection by 12 months of age were associated with the appearance of type 1 DMrelated autoimmunity among children who were exposed to cow's milk before 3 months of age. These results suggest an interaction between the 2 factors and provide a possible explanation for the contradictory findings obtained in studies that examined these factors in isolation. [25] One meta-analysis found a weak but significant linear increase in the risk of childhood type 1 DM with increasing maternal age.[26] However, little evidence supports any substantial increase in childhood type 1 DM risk after pregnancy complicated by preeclampsia.[27] A study by Simpson et al found that neither vitamin D intake nor 25-hydroxyvitamin D levels throughout childhood were associated with islet autoimmunity or progression to type 1 DM. [28] This study was based in Denver, Colorado, and has been following children at increased risk of diabetes since 1993.

Epidemiology
United States statistics
A 2011 report from the US Centers for Disease Control and Prevention (CDC) estimated that approximately 1 million Americans have type 1 DM.[29] The CDC estimated that each year from 2002 to 2005, type 1 DM was newly diagnosed in 15,600 young people. Among children younger than 10 years, the annual rate of new cases was 19.7 per 100,000 population; among those 10 years or older, the rate was 18.6 per 100,000 population. [29] Type 1 DM is the most common metabolic disease of childhood. About 1 in every 400-600 children and adolescents has type 1 DM. In adults, type 1 DM constitutes approximately 5% of all diagnosed cases of diabetes. [29]

International statistics
Internationally, rates of type 1 DM are increasing. In Europe, the Middle East, and Australia, rates of type 1 DM are increasing by 2-5% per year.[30] The prevalence of type 1 DM is highest in Scandinavia (ie, approximately 20% of the

total number of people with DM) and lowest in China and Japan (ie, fewer than 1% of all people with diabetes). Some of these differences may relate to definitional issues and the completeness of reporting.

Age-related demographics
Previously referred to as juvenile-onset diabetes, type 1 DM is typically diagnosed in childhood, adolescence, or early adulthood. Although the onset of type 1 DM often occurs early in life, 50% of patients with new-onset type 1 DM are older than 20 years of age. Type 1 DM usually starts in children aged 4 years or older, appearing fairly abruptly, with the peak incidence of onset at age 11-13 years (ie, in early adolescence and puberty). There is also a relatively high incidence in people in their late 30s and early 40s, in whom the disease tends to present less aggressively (ie, with early hyperglycemia without ketoacidosis and gradual onset of ketosis). This slower-onset adult form of type 1 DM is referred to as latent autoimmune diabetes of the adult (LADA).[29] The risk of development of antibodies (anti-islet) in relatives of patients with type 1 DM decreases with increasing age. This finding supports annual screening for antibodies in relatives younger than 10 years and 1 additional screening during adolescence.[31]

Sex- and race-related demographics

Type 1 DM is more common in males than in females. In populations of European origin, the male-to-female ratio is greater than 1.5:1. Type 1 DM is most common among non-Hispanic whites, followed by African Americans and Hispanic Americans. It is comparatively uncommon among Asians.

Prognosis
Type 1 DM is associated with a high morbidity and premature mortality. More than 60% of patients with type 1 DM do not develop serious complications over the long term, but many of the rest experience blindness, end-stage renal disease (ESRD), and, in some cases, early death. The risk of ESRD and proliferative retinopathy is twice as high in men as in women when the onset of diabetes occurred before age 15 years. [32] Patients with type 1 DM who survive the period 10-20 years after disease onset without fulminant complications have a high probability of maintaining reasonably good health. Other factors affecting long-term outcomes are the patients education, awareness, motivation, and intelligence level. The 2012 American Diabetes Association (ADA) standard of care emphasizes the importance of long-term, coordinated care management for improved outcomes and suggests structural changes to existing systems of long-term care delivery.[33] The morbidity and mortality associated with diabetes are related to the short- and long-term complications. Such complications include the following:

Hypoglycemia from management errors Increased risk of infections Microvascular complications (eg, retinopathy and nephropathy) Neuropathic complications Macrovascular disease These complications result in increased risk for ischemic heart disease, cerebral vascular disease, peripheral vascular disease with gangrene of lower limbs, chronic renal disease, reduced visual acuity and blindness, and autonomic and peripheral neuropathy. Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and ESRD. In both diabetic and non-diabetic patients, coronary vasodilator dysfunction is a strong independent predictor of cardiac mortality. In diabetic patients without coronary artery disease, those with impaired coronary flow reserve have event rates similar to those with prior coronary artery disease, while patients with preserved coronary flow reserve have event rates similar to non-diabetic patients.[34] Although ESRD is one of the most severe complications of type 1 DM, its incidence is relatively low: 2.2% at 20 years after diagnosis and 7.8% at 30 years after diagnosis.[35] A greater risk is that mild diabetic nephropathy in type 1 diabetic persons appears to be associated with an increased likelihood of cardiovascular disease. [36] Moreover, the long-term risk of an impaired glomerular filtration rate (GFR) is lower in persons treated with intense insulin therapy early in the course of disease than in those given conventional therapy. [37]

Although mortality from early-onset type 1 DM (onset age, 0-14 y) has declined, the same may not be true for lateonset type 1 DM (onset age, 15-29 y). One study suggest that women tend to fare worse in both cohorts and that alcohol and drug use account for more than one third of deaths. [38] Control of blood glucose, hemoglobin A1c (HbA1c), lipids, blood pressure, and weight significantly affects prognosis. Patients with diabetes face a lifelong challenge to achieve and maintain blood glucose levels as close to the normal range as possible. With appropriate glycemic control, the risk of both microvascular and neuropathic complications is decreased markedly. In addition, aggressive treatment of hypertension and hyperlipidemia decreases the risk of macrovascular complications. The benefits of glycemic control and control of comorbidities must be weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. However, studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years of starting effective preventive care.

Patient Education
Education is a vital aspect of diabetes management. Patients with new-onset type 1 DM require extensive education if they are to manage their disease safely and effectively and to minimize long-term complications. Such education is best coordinated by the patients long-term care providers. At every encounter, the clinician should educate the patientand, in the case of children, the parentsabout the disease process, management, goals, and long-term complications. In particular, clinicians should do the following:

Make patients aware of the signs and symptoms of hypoglycemia and knowledgeable about ways to manage it Help patients understand and acknowledge the course of diabetes (eg, by teaching patients that they have a chronic condition that requires lifestyle modification and that they are likely to have chronic complications if they do not take control of their disease) Reassure patients about the prognosis in properly managed type 1 DM ADA guidelines urge that attention be paid to older adolescent patients who may be leaving their home and their current health care providers. At the transition between pediatric and adult health care, older teens can become detached from the health care system, putting their medical care and their glycemic control at risk. [33] The guidelines identify the National Diabetes Education Program (NDEP)as a source of materials that can help smooth the transition to adult health care. Education about an appropriate treatment plan and encouragement to follow the plan are especially important in patients with diabetes. Physicians must ensure that the care for each patient with diabetes includes all necessary laboratory tests, examinations (eg, foot and neurologic examinations), and referrals to specialists (eg, an ophthalmologist or podiatrist). A dietitian should provide specific diet control education to the patient and family. A nurse should educate the patient about selfinsulin injection and performing fingerstick tests for blood glucose level monitoring. For patient education information, see the Diabetes Center, as well as Diabetes

History
The most common symptoms of type 1 diabetes mellitus (DM) are polyuria, polydipsia, and polyphagia, along with lassitude, nausea, and blurred vision, all of which result from the hyperglycemia itself. Polyuria is caused by osmotic diuresis secondary to hyperglycemia. Severe nocturnal enuresis secondary to polyuria can be an indication of onset of diabetes in young children. Thirst is a response to the hyperosmolar state and dehydration. Fatigue and weakness may be caused by muscle wasting from the catabolic state of insulin deficiency, hypovolemia, and hypokalemia. Muscle cramps are caused by electrolyte imbalance. Blurred vision results from the effect of the hyperosmolar state on the lens and vitreous humor. Glucose and its metabolites cause osmotic swelling of the lens, altering its normal focal length. Symptoms at the time of the first clinical presentation can usually be traced back several days to several weeks. However, beta-cell destruction may have started months, or even years, before the onset of clinical symptoms. The onset of symptomatic disease may be sudden. It is not unusual for patients with type 1 DM to present with diabetic ketoacidosis (DKA), which may occur de novo or secondary to the stress of illness or surgery. An explosive onset of symptoms in a young lean patient with ketoacidosis always has been considered diagnostic of type 1 DM.

Over time, patients with new-onset type 1 DM will lose weight, despite normal or increased appetite, because of depletion of water and a catabolic state with reduced glycogen, proteins, and triglycerides. Weight loss may not occur if treatment is initiated promptly after the onset of the disease. Gastrointestinal (GI) symptoms of type 1 DM are as follows:

Nausea, abdominal discomfort or pain, and change in bowel movements may accompany acute DKA Acute fatty liver may lead to distention of the hepatic capsule, causing right upper quadrant pain Persistent abdominal pain may indicate another serious abdominal cause of DKA (eg, pancreatitis Chronic GI symptoms in the later stage of DM are caused by visceral autonomic neuropathy Neuropathy affects up to 50% of patients with type 1 DM, but symptomatic neuropathy is typically a late development, developing after many years of chronic prolonged hyperglycemia. Peripheral neuropathy presents as numbness and tingling in both hands and feet, in a glove-and-stocking pattern; it is bilateral, symmetric, and ascending.

History in patients with established diabetes

It is important to inquire about the type and duration of the patients diabetes and about the care the patient is receiving for diabetes. Determination of the type of diabetes is based on history, therapy, and clinical judgment. The chronic complications of diabetes are related to the length of time the patient has had the disease. Ask about the type of insulin being used, delivery system (pump vs injections), dose, and frequency. Also ask about oral antidiabetic agents, if any. Of course, a full review of all medications and over-the-counter supplements being taken is crucial in the assessment of patients with type 1 DM. Patients using a pump or a multiple-injection regimen have a basal insulin (taken through the pump or with the injection of a long-acting insulin analogue) and a premeal rapid-acting insulin, the dose of which may be determined as a function of the carbohydrate count plus the correction (to adjust for how high the premeal glucose level is). In these patients, ask about the following:

Basal rates (eg, units per hour by pump, generally 0.4-1.5 U/h, potentially varying on the basis of time of day); the total daily dose as basal insulin is a helpful value to know Carbohydrate ratio (ie, units of insulin per grams of carbohydrate, generally 1 unit of rapid-acting insulin per 10-15 g carbohydrate) Correction dose (ie, how far the blood glucose level is expected to decrease per unit of rapid-acting insulin, often 1 U of insulin per 50-mg/dL decrease, though individuals with insulin resistance may need 1 U per 25-mg/dL decrease) Some patients may be taking premeal pramlintide (an amylin analogue) A focused diabetes history should also include the following questions:

Is the patients diabetes generally well controlled, with near-normal blood glucose levels? (Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications) Does the patient have severe hypoglycemic reactions? (If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness, this possibility must be addressed, especially if the patient drives) Does the patient have diabetic nephropathy that might alter the use of medications or intravenous (IV) radiographic contrast material? Does the patient have macrovascular disease, such as coronary artery disease (CAD), which should be considered in the emergency department (ED)? Does the patient self-monitor his or her blood glucose levels? (Note the frequency and range of values at each time of day; an increasing number of patients monitor with continuous sensors) When was the patients hemoglobin A1c (HbA1c) value (an indicator of long-term glucose control) last measured? What was it? In assessing glycemic exposure of a patient with established type 1 DM, review of self-monitored blood glucose levels is necessary. Ideally, this done by uploading time- and date-stamped levels from the patients meter to assure full understanding of the frequency of testing and the actual levels.

Questions regarding hypoglycemia and hyperglycemia

Hypoglycemia and hyperglycemia should be considered. Ask the following questions as needed:

Has the patient experienced recent polyuria, polydipsia, nocturia, or weight loss? Has the patient had episodes of unexplained hypoglycemia? If so, when, how often, and how does the patient treat these episodes?

Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia)? (Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia)

Questions regarding microvascular complications

Microvascular complications, such as retinopathy and nephropathy, should be considered as well. Ask the following questions as appropriate:

When was the patients last dilated eye examination? What were the results? Does the patient have known kidney disease? What were the dates and results of the last measurements of urine protein and serum creatinine levels?

Questions regarding macrovascular complications

Macrovascular complications should be explored. Questions should include the following:

Does the patient have hypertension? What medications are taken? Does the patient have symptoms of claudication or a history of vascular bypass? Has the patient had a stroke or transient ischemic attack? What are the patients most recent lipid levels? Is the patient taking lipid-lowering medication?

Questions regarding neuropathy

Potential neuropathy should be taken into account. Ask whether the patient has a history of neuropathy or symptoms of peripheral neuropathy or whether autonomic neuropathy is present (including erectile dysfunction if the patient is a man).

Other questions
The possibility of foot disease should be addressed. Inquire as to whether the patient has a history of foot ulcers or amputations or whether any foot ulcers are present. (See Diabetic Foot and Diabetic Foot Infections.) The possibility of infection also should be considered. Be sure to inquire about whether frequent infections are a problem and, if so, at what sites.

Physical Examination
In new cases of diabetes, physical examination findings are usually normal. Patients with DKA, however, will have Kussmaul respiration, signs of dehydration, hypotension, and, in some cases, altered mental status. In established cases, patients should be examined every 3 months for macrovascular and microvascular complications. They should undergo funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy.

Diabetes-focused examination
A diabetes-focused physical examination includes assessment of vital signs, funduscopic examination, limited vascular and neurologic examinations, and foot examination. Other organ systems should be assessed as indicated by the patients clinical situation. A comprehensive examination is not necessary at every visit. Assessment of vital signs Patients with established diabetes and autonomic neuropathy may have orthostatic hypotension. Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy. Measurement of the pulse is important, in that relative tachycardia is a typical finding in autonomic neuropathy, often preceding the development of orthostatic hypotension. If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered immediately, and appropriate tests must be ordered. Funduscopic examination The funduscopic examination should include a careful view of the retina. Both the optic disc and the macula should be visualized. If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, which cannot be evaluated accurately unless the patients pupils are dilated. Foot examination

The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections: poor lower-extremity blood flow can delay healing and increase the risk of amputation. Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patients ability to protect the feet and ankles. If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation. (See Diabetic Foot andDiabetic Foot Infections.)

Complications
Infections
Infections cause considerable morbidity and mortality in patients with diabetes. Infection may precipitate metabolic derangements, and conversely, the metabolic derangements of diabetes may facilitate infection. (See Infections in Patients with Diabetes Mellitus.) Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resultant poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury. Diabetes increases susceptibility to various types of infections. The most common sites are the skin and urinary tract. Dermatologic infections that occur with increased frequency in patients with diabetes include staphylococcal follicular skin infections, superficial fungal infections, cellulitis, erysipelas, and oral or genital candidal infections. Both lower urinary tract infections and acute pyelonephritis are seen with greater frequency. A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes, though they are fairly rare even in this population. Infections such as staphylococcal sepsis occur more frequently and are more often fatal in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and other patients with the same frequency and severity.[39]

Ophthalmologic complications
Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to seek emergency care. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period. Patients with diabetes tend to develop senile cataracts at a younger age than persons without diabetes. Rarely, patients with type 1 DM that is very poorly controlled (eg, those with frequent episodes of DKA) can acutely develop a snowflake (or metabolic) cataract. Named for their snowflake or flocculent appearance, these cataracts can progress rapidly and create total opacification of the lens within a few days. Whether diabetes increases the risk of glaucoma remains controversial; epidemiologic studies have yielded conflicting results.[40] Glaucoma in diabetes relates to the neovascularization of the iris (ie, rubeosis iridis diabetica). Diabetic retinopathy is the principal ophthalmologic complication of DM. (SeeDiabetic Retinopathy.) Diabetic retinopathy is the leading cause of blindness in the United States in people younger than 60 years and affects the eyes in the following different ways:

Background retinopathy involves retinal small vessel abnormality leading to hard exudates, hemorrhages, and microaneurysms; it does not affect acuity Proliferative retinopathy involves extensive proliferation of new retinal small blood vessels; a sudden loss of vision can occur because of vitreous hemorrhage from proliferating new vessels or retinal detachment Maculopathy involves edema and hard exudate or retinal ischemia; it causes a marked reduction of acuity Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control.[41, 42, 43] The following are the 5 stages in the progression of diabetic retinopathy: 1. 2. Dilation of the retinal venules and formation of retinal capillary microaneurysms Increased vascular permeability

3. 4. 5.

Vascular occlusion and retinal ischemia Proliferation of new blood vessels on the surface of the retina Hemorrhage and contraction of the fibrovascular proliferation and the vitreous

The first 2 stages of diabetic retinopathy are jointly referred to as background or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. The microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina. The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision. (See Macular Edema in Diabetes .) Preproliferative (stage 3) and proliferative diabetic retinopathy (stages 4 and 5) are the next phases in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts from capillary occlusion and appear as off-white to gray patches with poorly defined margins. Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous.

Diabetic nephropathy
About 2030% of patients with type 1 DM develop evidence of nephropathy, [44] and all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Chronically elevated blood pressure contributes to the decline in renal function. The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Although most recover from contrast mediuminduced renal failure within 10 days, some have irreversible renal failure. (See Diabetic Nephropathy.)

Diabetic neuropathy
In the peripheral nerves, diabetes causes peripheral neuropathy. (See Diabetic Lumbosacral Plexopathy and Diabetic Neuropathy.) The 4 types of diabetic neuropathy are as follows:

Peripheral distal symmetrical polyneuropathy, predominantly sensory Autonomic neuropathy Proximal painful motor neuropathy Cranial mononeuropathy (ie, cranial nerve III, IV, or VI) Of these 4 types, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most common.[45] Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation. Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear). Patients can present with diplopia and eye pain. In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases. It is important to consider nondiabetic causes of cranial nerve palsies, including intracranial tumors, aneurysms, and brainstem stroke.[46] Therefore, evaluation should include nonenhanced and contrast-enhanced compute4d tomography (CT) or, preferably, magnetic resonance imaging (MRI). Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies.

Macrovascular complications

People with diabetes experience accelerated atherosclerosis, affecting the small arteries of the heart, brain, lower extremity, and kidney. Coronary atherosclerosis often occurs at a younger age and is more severe and extensive than in those without diabetes, increasing the risk of ischemic heart disease. Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia. Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease; these result from the involvement of much smaller and more peripheral arteries. Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia, which is a significant component of multiple renal lesions in diabetes. However, not all people with type 1 DM are at risk for nephropathy, because there are some polymorphisms in the various factors involved in its pathogenesis, which can modulate the course of this disease from one person to the other. Risk factors for macrovascular disease Macrovascular disease is the leading cause of death in patients with diabetes, causing 65-75% of deaths in this group, compared with approximately 35% of deaths in people without diabetes. Diabetes by itself increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well. The HbA1c value per se, rather than self-reported diabetes status or other established risk factors, robustly predicts MI odds. Each 1% increment in HbA1c independently predicts 19% higher odds for MI. [47] The risk of stroke in people with diabetes is double that of nondiabetic people, and the risk of peripheral vascular disease is 4 times that of people without diabetes. Patients with diabetes may have an increased incidence of silent ischemia. [48]Diastolic dysfunction is common in patients with diabetes and should be considered in patients who have symptoms of congestive heart failure and a normal ejection fraction.

Diagnostic Considerations
The following conditions and factors should be taken into account in considering a diagnosis of type 1 diabetes mellitus (DM):

Type 2 DM Monogenic DM,[49] previously known as maturity-onset diabetes of youth (MODY), a rare autosomal dominant condition found primarily in whites Secondary hyperglycemia Disorders of target tissues (liver, muscles, adipose tissue) Endocrine disorders - Endocrine tumor causing increased production of growth hormone, glucocorticoids, catecholamines, glucagon, and somatostatin; Addison disease; Graves disease; Hashimoto thyroiditis; acanthosis nigricans (genetic disorders with insulin resistance) Drugs - Thiazide diuretics, phenytoin, and glucocorticoids Chronic pancreatitis Cystic fibrosis Prader-Willi syndrome - Mental retardation, muscular hypotonia, obesity, short stature, and hypogonadism associated with DM Nondiabetic glycosuria Renal glycosuria - Glucose appears in urine despite normal glucose concentration in blood; this may occur because of an autosomal genetic disorder or dysfunction of the proximal renal tubule (eg, Fanconi syndrome or chronic renal failure), or it may occur during pregnancy as a consequence of the increased glucose load placed on tubules by the elevated glucose filtration rate Peripheral neuropathy from alcohol abuse or vitamin B-12 deficiency Type 1 versus type 2 diabetes Determining whether a patient has type 1 or type 2 DM is an important diagnostic and therapeutic concern because patients with type 1 DM depend on continuous exogenous insulin for survival. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 DM. A lean patient who has had diabetes since childhood, who has always been dependent on insulin, or who has a history of diabetic ketoacidosis (DKA) almost certainly has type 1 DM.

Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and who are younger but clinically appear to have type 2 DM and (2) older patients with late-onset diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 DM. (This latter group is now said to have latent autoimmune diabetes of the adult [LADA].) It should be noted that for many patients, it will not be possible to fully distinguish type 1 DM from type 2. When in doubt, treat the patient with insulin and close monitoring of glucose levels. It is not unusual for adolescents or young adults, particularly Hispanic or African-American patients, to present with DKA and subsequently be found to have type 2 DM. Monogenic diabetes Although monogenic diabetes syndromes are not very common, representing fewer than 5% of pediatric diabetes cases, it is important to avoid misdiagnosis of monogenic DM as type 1 or type 2 DM. The American Diabetes Association (ADA) advises considering a diagnosis of monogenic diabetes when the following criteria are present [33] :

Diabetes is diagnosed within 6 months of birth A strong family history of diabetes is present, without type 2 features (eg, obesity or higher-risk ethnicity) Mild fasting hyperglycemia is observed, especially in young, nonobese children Diabetes is present, but islet cell autoantibodies, obesity, and insulin resistance are absent If a form of monogenic diabetes is suspected, it is increasingly feasible to obtain a true genetic diagnosis through commercially available genetic testing. For further information about the diagnosis and management of monogenic diabetes, the ADA suggests consulting the 2009 clinical practice consensus guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) at the ISPAD website.[33, 50]

Differential Diagnoses

Diabetes Mellitus, Type 2 Diabetic Ketoacidosis Diabetic Nephropathy Diabetic Ulcers Insulin Resistance Lead Nephropathy

Laboratory Studies
Plasma glucose
Patients with type 1 diabetes mellitus (DM) typically present with symptoms of uncontrolled hyperglycemia (eg, polyuria, polydipsia, polyphagia). In such cases, the diagnosis of DM can be confirmed with a random (nonfasting) plasma glucose concentration of 200 mg/dL or a fasting plasma glucose concentration of 126 mg/dL (6.99 mmol/L) or higher.[51, 49] A fingerstick glucose test is appropriate in the emergency department (ED) for virtually all patients with diabetes. All fingerstick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis. All other laboratory studies should be selected or omitted on the basis of the individual clinical situation. Intravenous (IV) glucose testing may be considered for possible early detection of subclinical diabetes. Individually measured glucose levels may differ considerably from estimated glucose averages calculated from measured hemoglobin A1c (HbA1c) levels.[52]Therefore, caution is urged when the decision is made to estimate rather than actually measure glucose concentration; the difference between the 2 has a potential impact on decision making.

Hemoglobin A1c
HbA1c is the stable product of nonenzymatic irreversible glycation of the beta chain of hemoglobin by plasma glucose and is formed at rates that increase with increasing plasma glucose levels. HbA 1c levels provide an estimate of plasma glucose levels during the preceding 1-3 months. The reference range for nondiabetic people is 6% in most laboratories. Glycated hemoglobin levels also predict the progression of diabetic microvascular complications. American Diabetes Association (ADA) guidelines recommend measuring HbA1c at least every 6 months in patients with diabetes who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA1c testing every 3 months.[33]

In the past, HbA1c measurements were not considered useful for the diagnosis of DM. Drawbacks included a lack of international standardization and insensitivity for the detection of milder forms of glucose intolerance. In a 2009 report, however, an international expert committee appointed by the ADA, the European Association for the Study of Diabetes, and the International Diabetes Association recommended the HbA1c assay for diagnosing type 1 and type 2 DM.[53] In the case of type 1 DM, however, the committee recommended using the test only when the condition is suspected but the classic symptoms of type 1 DMpolyuria, polydipsia, polyphagia, a random glucose level of 200 mg/dL, and unexplained weight lossare absent. The committee noted the improvement in standardization and cited the following advantages of HbA 1c testing over glucose measurement:

Ability to capture long-term glucose exposure Less biologic variability No requirement for fasting or timed samples Current use in guiding management decisions Consequently, since 2010 the ADA has included an HbA1c level of 6.5% or higher as a criterion for diabetes diagnosis, with confirmation from repeat testing (unless clinical symptoms are present and the glucose level exceeds 200 mg/dL). HbA1ctesting cannot be used in patients with abnormal red blood cell (RBC) turnover (as in hemolytic or iron-deficiency anemia). In children with rapidly evolving type 1 DM, HbA 1c may not be significantly elevated despite frank diabetes.[51] One study found seasonal variability in HbA1c levels of school-age children with higher levels (0.44%) coinciding with colder outdoor temperatures, fewer hours of sunlight, and lower levels of solar irradiance. [54] This effect was seen in school-aged children but not preschoolers and may hold importance for studies using HbA 1c as a primary endpoint and HbA1c -based diagnosis of diabetes. HbA1c cannot be used as an indicator of glycemic control in patients with neonatal diabetes mellitus (NDM) because of the high levels of fetal hemoglobin (HbF) remaining in the blood. A study by Suzuki et al found that glycated albumin, which is not affected by HbF levels, more strongly correlated with 1-month average postprandial blood glucose and was therefore a better marker of diabetes in neonates. This finding is important to neonatologist and those caring for newborns.[55] ADA guidelines recommend measuring HbA1c at least every 6 months year in patients who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA1c testing every 3 months.[33]

Other laboratory studies

Fructosamine levels also test for glucose levels. Fructosamine is formed by a chemical reaction of glucose with plasma protein and reflects glucose control in the previous 1-3 weeks. This assay, therefore, may show a change in control before HbA1c and often is helpful when applying intensive treatment and in short-term clinical trials. A white blood cell (WBC) count and blood and urine cultures may be performed to rule out infection. Urine ketones are not reliable for diagnosing or monitoring diabetic ketoacidosis (DKA), although they may be useful in screening to see whether a hyperglycemic individual may have some degree of ketonemia. The plasma acetone levelspecifically, the beta-hydroxybutyrate levelis a more reliable indicator of DKA, along with measurement of plasma bicarbonate or arterial pH as clinically required. Screening for type 1 DM in asymptomatic low-risk individuals is not recommended.[51] However, in patients at high risk (eg, those who have first-degree relatives with type 1 DM), it may be appropriate to perform annual screening for antiislet antibodies before the age 10 years, along with 1 additional screening during adolescence. [31]

Tests to Differentiate Type 1 from Type 2 Diabetes

Although the oral glucose tolerance test with insulin levels is usually considered unnecessary for diagnosing type 1 DM, the dramatic increase of type 2 DM in the young suggests that assessment of insulin secretion may become more important. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines note that to help distinguish between the 2 types in children, physicians should measure insulin and C-peptide levels and immune markers (eg, glutamic acid decarboxylase [GAD] autoantibodies), as well as obtain a detailed family history. [49] C-peptide is formed during conversion of proinsulin to insulin. An insulin or C-peptide level below 5 U/mL (0.6 ng/mL) suggests type 1 DM; a fasting C-peptide level greater than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 (ie, residual beta-cell function). An exception is the individual with type 2 DM

who presents with a very high glucose level (eg, >300 mg/dL) and a temporarily low insulin or C-peptide level but who will recover insulin production once normal glucose is restored. Most patients who present with undiagnosed type 1 DM have the classic symptoms of uncontrolled hyperglycemia, including polyuria, polydipsia, nocturia, fatigue, and weight loss. In these patients, a confirmatory random plasma glucose level of greater than 200 mg/dL is adequate to establish the diagnosis of DM. On occasion, a patient who is ultimately found to have type 1 DM presents with subtle symptoms because of residual insulin secretion. Islet-cell (IA2), anti-GAD65, and anti-insulin autoantibodies can be present in early type 1 but not type 2 DM. Measurements of IA2 autoantibodies within 6 months of diagnosis can help differentiate between type 1 and type 2 DM. These titers decrease after 6 months. Anti-GAD65 antibodies can be present at diagnosis of type 1 DM and are persistently positive over time. (See also Type 2 Diabetes Mellitus.) Testing for islet autoantibodies can substitute for expensive genetic testing in those patients suspected of having maturity-onset diabetes of the young (MODY). The prevalence of these antibodies is the same in patients with MODY as in the healthy population. A positive test for positive islet autoantibodies makes MODY highly unlikely.[56]

Approach Considerations
Patients with type 1 diabetes mellitus (DM) require lifelong insulin therapy. Most require 2 or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. Long-term management requires a multidisciplinary approach that includes physicians, nurses, dietitians, and selected specialists. In some patients, the onset of type 1 DM is marked by an episode of diabetic ketoacidosis (DKA) but is followed by a symptom-free honeymoon period in which the symptoms remit and the patient requires little or no insulin. This remission is caused by a partial return of endogenous insulin secretion, and it may last for several weeks or months (sometimes for as long as 1-2 years). Ultimately, however, the disease recurs, and patients require insulin therapy. Often, the patient with new-onset type 1 DM who presents with mild manifestations and who is judged to be compliant can begin insulin therapy as an outpatient. However, this approach requires close follow-up and the ability to provide immediate and thorough education about the use of insulin; the signs, symptoms, and treatment of hypoglycemia; and the need to self-monitor blood glucose levels. The American Diabetes Association (ADA) recommends using patient age as one consideration in the establishment of glycemic goals, with different targets for preprandial, bedtime/overnight, and hemoglobin A 1c (HbA1c) levels in patients aged 0-6, 6-12, and 13-19 years.[33] Goals should be further individualized on the basis of awareness of hypoglycemia, frequency of hypoglycemia, and response to treatment. Although patients with type 1 DM have normal incretin response to meals, administration of exogenous glucagonlike peptide 1 (GLP-1) reduces peak postprandial glucose by 45%. Long-term effects of exogenously administered GLP-1 analogues warrant further studies.[57] Pancreatic transplantation for patients with type 1 DM isg a possibility in some referral centers. It is performed most commonly with simultaneous kidney transplantation for end-stage renal disease (ESRD).

Tight glycemic control

The association between chronic hyperglycemia and increased risk of microvascular complications in patients with type 1 DM was demonstrated in the Diabetes Control and Complications Trial (DCCT). [58] In that trial, intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, proteinuria, and neuropathy, as assessed over 7 years. The DCCT ended in 1993. However, the Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, has demonstrated continued benefit from intensive treatment.[59, 60] Benefits Benefits of tight glycemic control include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality. These benefits occurred even though subjects in the intensively treated group and those in the standard treatment group maintained similar HbA1c levels (about 8%), starting 1 year after the DCCT ended. It is postulated that a metabolic memory exists and that better early glycemic control sets the stage for outcomes many years in the future. Increasing HbA1c levels correlated with increasing risk of developing heart failure in a study of 20,985 patients with type 1 DM. Thus, improved glycemic control should prevent heart failure as well. [61]

Risks For many patients, the HbA1c target should be less than 7%, with a premeal blood glucose level of 80130 mg/dL. However, targets should be individualized. Individuals with recurrent episodes of severe hypoglycemia, cardiovascular disease, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an HbA 1c of less than 8% and preprandial glucose levels of 100-150 mg/dL. The 2011 American Association of Clinical Endocrinologists (AACE) guidelines support the creation of individualized targets that consider these factors as part of a comprehensive treatment plan.[62] Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. The 2011 AACE guidelines for developing a comprehensive care plan emphasize that hypoglycemia should be avoided.[49] In patients with type 1 DM, recurrent and chronic hypoglycemia has been linked to cognitive dysfunction.[63] This has important implications in the management of children with type 1 DM. [64] An 18-year follow-up of the DCCT by Jacobson et al found that HbA1c levels and retinal and renal complications were independently linked to cognitive declines. No relation with macrovascular risk factors or severe hypoglycemic events was found. A smoking history was modestly associated with decrements in learning, memory, spatial information processing, and psychomotor efficiency. This information is useful in advising patients with type 1 DM interested in preserving cognitive function.

Self-Monitoring of Glucose Levels

Optimal diabetic control requires frequent self-monitoring of blood glucose levels, which allows rational adjustments in insulin doses. All patients with type 1 DM should learn how to self-monitor and record their blood glucose levels with home analyzers and adjust their insulin doses accordingly. Insulin-dependent patients ideally should test their plasma glucose daily before meals, in some cases 1-2 hours after meals, and at bedtime. In practice, however, patients often obtain 2-4 measurements each day, including fasting levels and levels checked at various other times (eg, preprandially and at bedtime). Instruct patients with type 1 DM in the method of testing for urine ketones with commercially available reagent strips. Advise patients to test for urine ketones whenever they develop any of the following:

Symptoms of a cold, flu, or other intercurrent illness Nausea, vomiting, or abdominal pain Polyuria An unexpectedly high plasma glucose level on self-monitoring Persistent, rapid, and marked fluctuation in the degree of hyperglycemia

Continuous glucose monitoring

Continuous glucose monitors (CGMs) contain subcutaneous sensors that measure interstitial glucose levels every 15 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling. CGMs transmit to a receiver, which either is a pagerlike device or is integral to an insulin pump. Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycemia or hypoglycemia. CGMs have several drawbacks. First, there is a lag between glucose levels in the interstitial space and levels in capillary blood, so that the levels recorded by the CGM may differ from a fingerstick (capillary) glucose reading. For that reason, the trends (ie, whether the glucose levels are rising or falling) tend to be more helpful. Second, patients may overtreat hyperglycemia (repeatedly giving insulin because the glucose levels do not fall rapidly enougha phenomenon known as stacking) as well as overtreat low glucose levels (because the glucose levels rise slowly with ingestion of carbohydrate). Use of CGMs may help prevent significant glucose variability in patients receiving either multiple daily injection therapy or continuous insulin infusion therapy.[65]Additionally, continuous glucose monitoring is associated with reduced time spent in hypoglycemia.[66] Whether glucose variability is detrimental in the absence of hypoglycemia remains an unresolved question; in any event, variability leads to the expense of frequent testing. Guidelines from the Endocrine Society[67] recommend the use of real-time CGMs in adult patients with type 1 DM who have demonstrated that they are able to use these devices on a nearly daily basis. The guidelines suggest the intermittent use of CGM systems for short-term retrospective analysis in the following cases[67] :

Patients with suspected nocturnal hypoglycemia, dawn phenomenon, or postprandial hyperglycemia Patients with hypoglycemic unawareness Patients experimenting with important changes to their diabetes regimen (eg, instituting new insulin or switching from multiple daily injections to pump therapy)

Insulin Therapy
Types of insulin
Rapid-, short-, intermediate-, and long-acting insulin preparations are available. Various pork, beef, and beef-pork insulins were previously used; however, in the United States, recombinant human insulin is now used almost exclusively. Commercially prepared mixtures of insulin are also available. Rapid-acting insulins include lispro, glulisine, and aspart insulin. Lispro insulin is a form of regular insulin that is genetically engineered with the reversal of the amino acids lysine and proline at B28,29 in the B chain. Glulisine insulin substitutes glutamic acid for lysine in position B29. Aspart insulin substitutes aspartic acid for proline in position 28 of the B chain. These insulins are absorbed more quickly and have a rapid onset of action (5-10 minutes), a short interval to peak action (45-75 minutes), and a short duration of action (2-4 hours). Therefore, they can be administered shortly before eating. In addition, neutral protamine Hagedorn (NPH) insulin will not inhibit the action of insulin lispro when the 2 agents are mixed together right before injection; this is not true of regular insulin. Short-acting insulin includes regular insulin. Regular insulin is a preparation of zinc insulin crystals in solution. When it is administered subcutaneously, its onset of action occurs in 0.5 hours, its peak activity comes at 2.5-5 hours, and its duration of action is 4-12 hours. The standard strength of regular insulin is 100 U/mL (U-100), but 500 U/mL (U-500) insulin is increasingly used, albeit mostly in type 2 DM. Accidental prescribing of U-500 rather than U-100 is a potential safety issue.[68] A study by de la Pena et al found that although the overall insulin exposure and effects of 500 U/mL insulin are similar to those of 100 U/mL insulin, peak concentration was significantly lower with U-500, and the effect after the peak was prolonged; areas under the curve were similar for the 2 strengths.[69] Both regular human insulin and rapid-acting insulin analogues are effective at lowering postprandial hyperglycemia in various basal bolus insulin regimens used in type 1 DM. Rapid-acting insulin analogues may be slightly better at lowering HbA1c and are preferred by most US diabetologists, but the differences are clinically insignificant. [70] Semilente insulin is like regular insulin and is a rapid-acting insulin with a slightly slower onset of action. It contains zinc insulin microcrystals in an acetate buffer. It is not readily available in the United States. Intermediate-acting insulins include NPH insulin, a crystalline suspension of human insulin with protamine and zinc. NPH provides a slower onset of action and longer duration of action than regular insulin does. The onset of action usually occurs at 1-2 hours, the peak effect is noted at 4-12 hours, and the duration of action is normally 1424 hours. Lente insulin is a suspension of insulin in buffered water that is modified by the addition of zinc chloride. This insulin zinc suspension is equivalent to a mixture of 30% prompt insulin zinc (Semilente) and 70% extended insulin zinc (Ultralente). It is not used in the United States. Long-acting insulins used in the United States include insulin glargine and insulin detemir. Insulin glargine has no peak and produces a relatively stable level lasting more than 24 hours. In some cases, it can produce a stable basal serum insulin concentration with a single daily injection, though patients requiring lower doses typically are given twice-daily injections. Insulin detemir has a duration of action that may be substantially shorter than that of insulin glargine but longer than those of intermediate-acting insulins. A new ultralong-acting basal insulin, insulin degludec, which has a duration of action of up to 42 hours, has been developed. It awaits approval by the US Food and Drug Administration (FDA). [71] Mixtures of insulin preparations with different onsets and durations of action frequently are administered in a single injection by drawing measured doses of 2 preparations into the same syringe immediately before use. The exceptions are insulin glargine and insulin detemir, which should not be mixed with any other form of insulin. Preparations that contain a mixture of 70% NPH and 30% regular human insulin (eg, Novolin 70/30 and Humulin 70/30) are available, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use. Insulin glargine and cancer

Controversy has arisen over a disputed link between insulin glargine and cancer. On July 1, 2009, the FDA issued an early communication regarding a possible increased risk of cancer in patients using insulin glargine (Lantus).[72] The FDA communication was based on 4 observational studies that evaluated large patient databases and found some association between insulin glargine (and other insulin products) and various types of cancer. The validity of the link remains in question, however. The duration of these observational studies was shorter than that considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. In a study by Suissa et al, insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use. The risk tended to increase after 5 years, however, and significantly so for the women who had taken other forms of insulin before starting insulin glargine. [73] A study by Johnson et al found the same incidences for all cancers in patients receiving insulin glargine as in those not receiving insulin glargine. Overall, no increase in breast cancer rates was associated with insulin glargine use, although patients who used only insulin glargine had a higher rate of cancer than those who used another type of insulin. This finding was attributed to allocation bias and differences in baseline characteristics. [74]

Common insulin regimens

The goal of treatment in type 1 DM is to provide insulin in as physiologic a manner as possible. Insulin replacement is accomplished by giving a basal insulin and a preprandial (premeal) insulin. The basal insulin is either long-acting (glargine or detemir) or intermediate-acting (NPH). The preprandial insulin is either rapid-acting (lispro, aspart, or glulisine) or short-acting (regular). Currently, NPH insulin is being used less frequently, whereas insulin glargine and insulin detemir are being used more frequently. For patients on intensive insulin regimens (multiple daily injections or insulin pumps), the preprandial dose is based on the carbohydrate content of the meal (the carbohydrate ratio) plus a correction dose if their blood glucose level is elevated (eg, an additional 2 U of rapid-acting insulin to correct the blood glucose from a level of 200 mg/dL to a target of 100 mg/dL). This method allows patients more flexibility in caloric intake and activity, but it requires more blood glucose monitoring and closer attention to the control of their diabetes. Common insulin regimens include the following:

Split or mixed NPH with rapid-acting (eg, lispro, aspart, or glulisine) or regular insulin before breakfast and supper Split or mixed variant NPH with rapid-acting or regular insulin before breakfast, rapid-acting or regular insulin before supper, and NPH before bedtime (the idea is to reduce fasting hypoglycemia by giving the NPH later in the evening) Multiple daily injections (MDI) A long-acting insulin (eg, glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients) and a rapid-acting insulin before meals or snacks (with the dose adjusted according to the carbohydrate intake and the blood glucose level) Continuous subcutaneous insulin infusion (CSII) Rapid-acting insulin infused continuously 24 hours a day through an insulin pump at 1 or more basal rates, with additional boluses given before each meal and correction doses administered if blood glucose levels exceed target levels Insulin is sensitive to heat and exposure to oxygen. Once a bottle of insulin is open, it should be used for no more than 28 days and then discarded; even if there is still some insulin in the bottle, it may have lost its clinical effectiveness. Insulin kept in a pump reservoir for longer than 3 days may lose its clinical effectiveness (though insulin aspart has now been approved for use for as long as 6 days in a pump). Sometimes, insulin distributed from the pharmacy has been exposed to heat or other environmental factors and therefore may be less active. If a patient is experiencing unexplained high blood sugar levels, new insulin vials should be opened and used.

Initiation of insulin therapy

The initial daily insulin dose is calculated on the basis of the patients weight. This dose is usually divided so that one half is administered before breakfast, one fourth before dinner, and one fourth at bedtime. After selecting the initial dose, adjust the amounts, types, and timing according to the plasma glucose levels. Adjust the dose to maintain preprandial plasma glucose at 80-150 mg/dL (ie, 4.44-8.33 mmol/L). The insulin dose is often adjusted in increments of 10% at a time, and the effects are assessed over about 3 days before any further changes are made. More frequent adjustments of regular insulin can be made if a risk of hypoglycemia is present.

Carbohydrate counting may be used to determine the meal-time insulin dose. Because patients may experience hyperglycemic episodes despite strict adherence to carbohydrate counting, particularly after meals that are high in protein or fat, Australian researchers developed an algorithm for estimating the mealtime insulin dose on the basis of measurements of physiologic insulin demand evoked by foods in healthy adults. The researchers showed that use of this algorithm improved glycemic control.[75] Initiation of insulin therapy in children Children with moderate hyperglycemia but without ketonuria or acidosis may be started with a single daily subcutaneous injection of 0.3-0.5 U/kg of intermediate-acting insulin alone. Children with hyperglycemia and ketonuria but without acidosis or dehydration may be started on 0.5-0.7 U/kg of intermediate-acting insulin and subcutaneous injections of 0.1 U/kg of regular insulin at 4- to 6-hour intervals. Multiple daily injections Multiple subcutaneous insulin injections are administered to control hyperglycemia after meals and to maintain normal plasma glucose levels throughout the day. This may increase the risks of hypoglycemia. Therefore, patients should be well educated about their disease and about self-monitoring of plasma glucose levels. About 25% of the total daily dose is administered as intermediate-acting insulin at bedtime, with additional doses of rapid-acting insulin before each meal (4-dose regimen). Where available, a basal insulin such as glargine or detemir is preferred to NPH. These patients may need additional intermediate- or long-acting insulin in the morning for all-day coverage. Patients should adjust their daily dosage(s) on the basis of their self-monitoring of glucose levels before each meal and at bedtime. Patients should also assess their plasma glucose levels at 2:00-4:00 AM at least once per week during the first few weeks of treatment and thereafter as indicated. Continuous subcutaneous insulin infusion A small battery-operated infusion pump that administers a continuous subcutaneous infusion of rapid-acting insulin can provide selected, programmed basal rate(s) of insulin and a manually administered bolus dose before each meal. The patient self-monitors preprandial glucose levels to adjust the bolus dose(s). The CSII method provides better control than the MDI method does. Initially, hypoglycemia is common with pump therapy, but once metabolic control is achieved, the risk is the same as with MDI. Bergenstal et al determined that sensor-augmented pump therapy led to better glycemic control and that more patients reached targets with this technology than with injection therapy.[76] Increased bedtime doses of hypoglycemic agents with nighttime peaks in action may correct early morning hyperglycemia but may be associated with undesirable nocturnal hypoglycemia. Targeted CSII programming can facilitate the prevention of early-morning hyperglycemia in selected patients. Changes in altitude may affect delivery from insulin pumps. During the flight of a commercial airliner (200 mm Hg pressure decrease), excess insulin delivery of 0.623% of cartridge volume was demonstrated as a result of bubble formation and expansion of preexisting bubbles.[77]

Local allergic reactions

Generalized insulin allergy is rare. Symptoms occur immediately after the injection and include urticaria, angioedema, pruritus, bronchospasm, and, rarely, circulatory shock. As a rule, allergy may be treated with antihistamines. Some cases may require epinephrine and intravenous (IV) steroids. Local allergic reactions can occur at the site of insulin injections and can cause pain, burning, local erythema, pruritus, and induration. These complications are less common with the human insulins now in use than with the animal insulins once widely employed. Such reactions usually resolve spontaneously without any intervention. Local fat atrophy or hypertrophy at injection sites was common with animal insulins but is rare with human insulin and insulin analogues. Patients do not require any specific treatment of local fat hypertrophy, but injection sites should be rotated. Changing to a different insulin preparation may be necessary.[78]

Management of Hypoglycemia
Hypoglycemia may result from a change in insulin dose, a small or missed meal, or strenuous exercise. Regular insulin doses may cause hypoglycemia if the patient becomes anorectic or has another cause for reduced food intake, has gastroparesis, or is vomiting.

Common symptoms of hypoglycemia are light-headedness, dizziness, confusion, shakiness, sweating, and headache. Patients should be made aware of these symptoms and educated to respond rapidly with sugar intake. They should be advised to carry candy or sugar cubes. Family members can be taught to administer a subcutaneous injection of glucagon. In an emergency situation, initial treatment consists of a bolus injection of 25 mL of 50% glucose solution followed by a continuous glucose infusion. Repeated hypoglycemia may be an aggravating factor in preclinical atherosclerosis. Thus, in the process of designing treatment plans aimed at reducing the glycemic burden and minimizing vascular complications, hypoglycemic episodes might negate some benefits.[79] Controversy surrounds the question of whether severe hypoglycemia in youths with type 1 DM has lasting cognitive consequences. In a follow-up to the DCCT, recurrent and chronic hypoglycemia was linked to cognitive dysfunction.[63] In another study, however, electroencephalography (EEG) and cognition studies were performed at baseline and 16 years later in patients with type 1 DM, and no association between early severe hypoglycemia and subsequent reduced adult cognition or EEG changes was found. [80]

Management of Hyperglycemia
Acute hyperglycemia, even when not associated with DKA (or hyperosmolar hyperglycemic state [HHS], which occurs most commonly in type 2 DM), is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose (which is typically 240 mg/dL in a healthy person but is lower in older patients, those with renal insufficiency, and pregnant women), an osmotic diuresis ensues, with loss of glucose, electrolytes, and water. In addition, hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection, and hyperglycemia impairs wound healing. In patients with known, poorly controlled type 1 DM, no absolute level of blood glucose elevation mandates admission to the hospital or administration of insulin in the emergency department (ED). In general, lowering the patients glucose level in the ED does not correct the underlying cause and has no long-term effect on the patients glucose levels. Therefore, a plan for lowering and monitoring the patients glucose levels is needed. Adequacy of follow-up is extremely important. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis. Patients with type 1 DM can have coexisting illnesses that aggravate hyperglycemia, such as infection, coronary artery disease (CAD), or fever. Additionally, certain medications can aggravate the condition.

Diabetic ketoacidosis
DKA involves acute metabolic changes in the body that develop as a result of lack of insulin or poor response to insulin arising from stress or illness. DKA is characterized by hyperglycemia, ketosis, and acidosis, leading to osmotic diuresis and dehydration. Volume repletion, insulin therapy, and specific metabolic corrections are the keys to treatment of DKA. (See Diabetic Ketoacidosis.)

Dawn and Somogyi phenomena

The dawn phenomenon is the normal tendency of the blood glucose to rise in the early morning before breakfast. This rise, which may result from the nocturnal spikes in growth hormone that cause insulin resistance, is probably enhanced by increased hepatic gluconeogenesis secondary to the diurnal rise in serum cortisol. Augmented hepatic gluconeogenesis and glycogen cycling are known to occur in patients with type 1 DM. However, both abnormalities, regardless of the duration of diabetes, can be corrected with intensified insulin therapy. [81] In some patients, however, nocturnal hypoglycemia may be followed by a marked increase in fasting plasma glucose with an increase in plasma ketones (the Somogyi phenomenon). Thus, both the dawn phenomenon and the Somogyi phenomenon are characterized by morning hyperglycemia, but the latter is considered to be rebound (counterregulation) hyperglycemia. The existence of a true Somogyi phenomenon is a matter of debate. Most endocrinologists now believe this phenomenon reflects waning of insulin action with consequent hyperglycemia. In cases of the dawn phenomenon, the patient should check blood glucose levels at 2:00-4:00 AM. The dawn and Somogyi phenomena can be ameliorated by administering intermediate insulin at bedtime.

Use of insulin

The insulin coverage, with a sliding scale for insulin administration, should not be the only intervention for correcting hyperglycemia, because it is reactive rather than proactive. Also, insulin may be used inappropriately when hyperglycemia reflects hepatic gluconeogenesis in response to previously uncorrected hypoglycemia. Continue intermediate-acting (ie, NPH or Lente) insulin at 50-70% of the daily dose divided into 2 or, occasionally, 3-4 daily doses. Administer supplemental regular insulin on a sliding scale. Blood glucose should be monitored before meals and at bedtime.

Diet
One of the first steps in managing type 1 DM is diet control. According to ADA policy, dietary treatment is based upon nutritional assessment and treatment goals. Dietary recommendations should take into account the patients eating habits and lifestyle. For example, patients who participate in Ramadan may be at higher risk of acute diabetic complications. Although these patients do not eat during the annual observance, they should be encouraged to actively monitor their glucose, alter the dosage and timing of their medication, and seek dietary counseling and patient education to counteract these complications.[82] Diet management includes education about how to adjust the timing, size, frequency, and composition of meals so as to avoid hypoglycemia or postprandial hyperglycemia. All patients on insulin should have a comprehensive diet plan, created with the help of a professional dietitian, that includes the following:

A daily caloric intake prescription Recommendations for amounts of dietary carbohydrate, fat, and protein Instructions on how to divide calories between meals and snacks Caloric distribution is an important aspect of dietary planning in these patients. A recommended distribution consists of 20% of daily calories for breakfast, 35% for lunch, 30% for dinner, and 15% for a late-evening snack. The minimum protein requirement for good nutrition is 0.9 g/kg/day (usual range, 1-1.5 g/kg/day), but a reduced protein intake is indicated in cases of nephropathy. Fat intake should be limited to no more than 30% of the total calories, and a low-cholesterol diet is recommended. Patients should minimize consumption of sugars and ensure that they have adequate fiber intake. In some cases, midmorning and midafternoon snacks are important to avoid hypoglycemia.

Activity
Exercise is an important aspect of diabetes management. Patients should be encouraged to exercise regularly. Educate the patients about the effects of exercise on the blood glucose level. If patients participate in rigorous exercise for more than 30 minutes, they may develop hypoglycemia unless they either decrease the preceding insulin injection by 10-20% or have an extra snack. Patients must also make sure to maintain their hydration status during exercise.

Management of Complications
Infections
Diabetes predisposes patients to a number of infectious diseases (see Infections in Patients with Diabetes Mellitus). These include the following:

Malignant otitis externa Rhinocerebral mucormycosis Bacteriuria Pyuria Cystitis Upper urinary tract infection Intrarenal bacterial infection Skin and soft tissue infections Osteomyelitis

Ophthalmologic complications
Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation. Laser therapy is effective in this condition, especially if it is provided before hemorrhage occurs.

Often, the first hemorrhage is small and is noted by the patient as a fleeting dark area (or floater) in the field of vision. Because subsequent hemorrhages can be larger and more serious, the patient should immediately be referred to an ophthalmologist for possible laser therapy. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping), so that the blood settles to the inferior portion of the retina and thus obscures less of the central visual area. Multifactorial intervention is important for slowing the progression of diabetic retinopathy. Metabolic control, smoking cessation, and blood pressure control are all protective. Patients with active proliferative diabetic retinopathy are at increased risk for retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents. (SeeDiabetic Retinopathy and Macular Edema in Diabetes.)

Diabetic nephropathy
Extreme care should be exercised whenever any nephrotoxic agent is used in a patient with diabetes. Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced doses appropriate to the patients serum creatinine level. (See Diabetic Nephropathy.) In particular, caution should be exercised when contrast-enhanced radiologic studies are being considered in patients with diabetes who have a creatinine level higher than 2 mg/dL. Indeed, such studies should absolutely be avoided in patients with a creatinine level higher than 3 mg/dL. Patients with diabetes who must undergo such studies should be well hydrated before, during, and after the study, and their renal function should be carefully monitored.[83] A better solution is to seek equivalent clinical information by using an alternative modality that does not require the use of contrast material (eg, ultrasonography, noncontrast computed tomography [CT], or magnetic resonance imaging [MRI]). Current ADA guidelines recommend annual screening for nephropathy. [33] All adults with diabetes should have serum creatinine measured at least annually. In adults (and children aged 10 years or older) who have had type 1 DM for 5 or more years, annual assessment of urine albumin excretion is appropriate. Microalbuminuria and macroalbuminuria are not permanent features in most diabetic children and adolescents.[84] Regression of microalbuminuria is common; female gender, absence of retinopathy, better glucose control, lower blood pressure, and better lipid control favor this outcome.[85] In patients with persistent microalbuminuria, the use of angiotensin-converting enzyme (ACE) inhibitors and good metabolic control can usually induce remission. Progression and regression of kidney disease are common even after development of persistent microalbuminuria. Tight glycemic control, lower blood pressure, and a favorable lipid profile are associated with improved outcome. [85] When chronic kidney disease is present, reduction of protein intake may improve renal function. If kidney disease is advanced or difficult to manage or its etiology is unclear, consider referral to a physician with experience in kidney disease patient care. Control of blood pressure is a critical element of care. An ACE inhibitor or an angiotensin II receptor blocker (ARB) should be used because these classes of agents decrease proteinuria and slow the decline in renal function independent of the effect on blood pressure.[86] ACE inhibitors and ARBs tend to increase the serum potassium levels and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels.

Diabetic neuropathy
Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations.[45, 87] Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, or symptomatic orthostatic hypotension. Treatment of gastroparesis is symptomatic, and symptoms tend to wax and wane. Patients with gastroparesis may benefit from metoclopramide or erythromycin. Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used. Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone. Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating for both doctor and patient. (See Diabetic Neuropathy and Diabetic Lumbosacral Plexopathy.)

Diabetic foot disease

Patients with diabetes who present with wounds, infections, or ulcers of the foot should be treated intensively. [88] In addition to appropriate use of antibiotics, the use of crutches, wheelchairs, or bed rest is mandatory for preventing

further trauma to the healing foot. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease. (See Diabetic Footand Diabetic Foot Infections.) If bone or tendon is visible, osteomyelitis is present, and hospitalization for IV antibiotic therapy is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing. Because ulcers and foot infections are difficult to cure, their prevention is extremely important.[89] At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. The emergency physician can facilitate this practice by briefly inspecting the feet of patients with diabetes and by educating them about the need for proper foot care. Referral to a podiatrist is indicated for diabetic patients with any of the following:

Distal sensory neuropathy with inability to feel a pinprick or light touch Decreased peripheral pulses Moderate-to-severe onychomycosis Impending skin breakdown Charcot joint, a type of arthropathy observed in people with diabetes, is a progressive deterioration of foot joints caused by underlying neuropathy. Tarsometatarsal and midtarsal joints are affected most commonly. Other neuromuscular foot deformities also may be present. Early diagnosis and treatment are important for preventing further joint degeneration.

Macrovascular disease
Hypercholesterolemia and hypertension increase the risk of specific late complications and require special attention and appropriate treatment. Although physicians can safely use beta blockers (eg, propranolol) in most patients, these agents can mask the adrenergic symptoms of insulin-induced hypoglycemia and can impair the normal counterregulatory response. ACE inhibitors are the drugs of choice for hypertension because of their renal protective action, especially early in the course of the disease. The ADA advises that a systolic blood pressure below 130 mm Hg is an appropriate goal for most patients with diabetes and hypertension, but it also recommends modifying systolic blood pressure targets in accordance with individual patient characteristics. Diastolic blood pressure should be less than 80 mm Hg.[33] Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. Therefore, lipid abnormalities must be treated aggressively to reduce the risk of serious atherosclerosis.[90] This is important from an epidemiologic point of view and has a bearing on the treatment strategies that must be used to mitigate the risk.[91] Prediction of cardiovascular risk in diabetic patients on the basis of the lipid profile is not affected by the timing of blood specimen. Therefore, it may be unnecessary to insist on using fasting blood samples to determine the lipid profile.[92] In a study involving diabetic adolescents and children, nocturnal hypertension was significantly associated with higher daytime blood pressure and carotid intima-media thickness, which could be precursors of atherosclerotic cardiovascular disease later in life; these findings warrant confirmation and longitudinal follow-up.[93] Patients with diabetes may have increased incidence of silent ischemia. [48]However, silent ischemia is common in many patients with CAD, and the apparent increase in its incidence may come about because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, it is prudent to perform electrocardiography (ECG) in patients who have diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not usually expected to result from myocardial ischemia. Persistent lipid abnormalities remain in patients with diabetes, despite evidence supporting the benefits of lipidmodifying drugs. Up-titration of the statin dose and addition of other lipid-modifying agents are needed.[94] Although metformin is used principally in type 2 DM because of its lipid-lowering effect, a placebo-controlled study by Lund et al found that metformin (1000 mg orally twice daily) significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with type 1 DM.[95]

Glycemic Control During Serious Medical Illness and Surgery

Serious medical illness and surgery produce a state of increased insulin resistance and relative insulin deficiency. Hyperglycemia can occur even in patients without diabetes as a consequence of stress-induced insulin resistance coupled with the use of dextrose-containing IV fluids. Increases in glucagon, catecholamines, cortisol, and growth

hormone levels antagonize the effects of insulin, and the alpha-adrenergic effect of increased catecholamine levels inhibits insulin secretion. Counterregulatory hormones also directly increase hepatic gluconeogenesis. Much less is known about optimal blood glucose levels in hospitalized patients with preexisting diabetes whose hyperglycemia reflects both their diabetes and a stress response to illness. Nonetheless, it is clear that management of hospitalized patients with preexisting diabetes requires modification of treatment regimens to compensate for both the decreased caloric intake and the increased physiologic stress. Near-normal blood glucose levels should be maintained in medical and surgical patients with diabetes, for the following reasons:

To prevent the development of ketosis To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis To prevent the impairment of leukocyte function that occurs when blood glucose levels are elevated To prevent the impairment of wound healing that occurs when glucose levels are elevated Patients with type 1 DM must take in insulin and carbohydrate at all times to prevent ketosis. It is strongly recommended that continuous IV infusions of dextrose and insulin be used in patients who are undergoing general anesthesia or who are critically ill. Blood glucose levels must be measured with a glucose meter every hour, and the rates of insulin and dextrose infusion must be adjusted accordingly to prevent hypoglycemia or persistent hyperglycemia. [96] Algorithms are available for insulin infusions, and the use of a preprinted order facilitates administration and reduces dosing errors. For patients who are less seriously ill or are undergoing minor surgery, frequentblood glucose monitoring is not always possible. These patients may do as well with subcutaneously injected insulin. A basal bolus insulin regimen, rather than a sliding-scale regular insulin regimen, should be used in these patients. The same principles of providing a constant source of insulin and carbohydrate apply to patients with type 1 DM who must also take nothing by mouth for medical reasons. Patients should receive a basal insulin (eg, glargine or detemir insulin) with additional correction doses of regular insulin or a rapid-acting insulin. In many localities, regular insulin has been replaced by rapid-acting insulin (eg, lispro, aspart, or glulisine) To prevent hypoglycemia, regular insulin should not be given more often than every 3-4 hours, because a dose is effective for up to 6 hours. Rapid-acting insulins may be given every 3 hours. Once the patient is eating, a preprandial insulin dose can be added. Cardiovascular disease or renal dysfunction increases surgical morbidity and mortality, and diabetic autonomic neuropathy increases the risk of cardiovascular instability. The emergency physician caring for patients with diabetes who require emergency surgery must notify the surgeon and the anesthesiologist of the patients condition, consult medical specialists when appropriate, and promptly initiate a thorough medical evaluation. Recent guidelines have trended away from stressing intensive glucose control in ill patients with diabetes. The ADA recommends that in critically ill patients, insulin therapy should be initiated if the glucose level exceeds 180 mg/dL (10 mmol/L), with a target range of 140-180 mg/dL (7.8-10 mmol/L) for the majority of critically ill patients. [33] More stringent goals, such as 110-140 mg/dL (6.1-7.8 mmol/L), may be appropriate for selected patients, provided that significant hypoglycemia can be avoided. In the absence of clear evidence for specific blood glucose goals in noncritically ill patients, the ADA suggests that reasonable targets are premeal blood glucose levels lower than 140 mg/dL (7.8 mmol/L) with random blood glucose levels below 180 mg/dL (10.0 mmol/L), provided that these targets can be safely achieved. [33] It may be appropriate to use more stringent targets in stable patients with previous tight glycemic control and less stringent targets in patients with severe comorbidities. The guidelines on glycemic control in hospitalized patients formulated by the American College of Physicians (ACP) recommend a target blood glucose level of 140-200 mg/dL if insulin therapy is used to manage patients with diabetes in nonsurgical (medical) intensive care units (ICUs).[97] These guidelines were based on a review of 21 trials in intensive care, perioperative care, myocardial infarction, stroke, or brain injury settings. [98] The ACP found no convincing evidence that intensive insulin therapy reduced short-term or long-term mortality, infection rates, length of hospital stay, or the need for renal replacement therapy. In recommending 200 mg/dL as the upper target, the ACP guidelines depart from the 2009 AACE/ADA consensus statement on inpatient glycemic control, which recommended a target range of 140-180 mg/dL in critically ill patients.[99] Nevertheless, in certain circumstances, such as after cardiovascular surgery and during treatment in a surgical ICU, it is very important to maintain near-normal blood glucose levels in patients with acute hyperglycemia of illness. These patients should receive sufficient insulin to maintain glucose levels around 100 mg/dL. [100]

Perioperative blood glucose management

Surgical proceduresincluding the preoperative emotional stress and the effects of general anesthesia as well as the trauma of the procedure itselfcan markedly increase plasma glucose levels and induce DKA in patients with type 1 DM. (SeePerioperative Management of the Diabetic Patient.) In patients going to surgery who have not received a dose of intermediate-acting insulin that day, injection of one third to one half of the total daily dose as NPH insulin or 80% of the dose as glargine or detemir insulin before surgery is often effective. At the same time, an IV infusion containing 5% glucose in either 0.9% saline solution or water should be started at a rate of 1 L (50 g glucose) over 6-8 hours (or 125-150 mL/h). Blood glucose levels should be checked every 2 hours during the surgical procedure, and small doses of regular or rapid-acting insulin (eg, lispro, aspart, or glulisine) should be given if values exceed 140 mg/dL. After the operation, check plasma glucose levels and assess for a reaction to ketones. Unless a change in dosage is indicated, repeat the preoperative dose of insulin when the patient recovers from the anesthesia, and continue the glucose infusion. Monitor plasma glucose and ketones at 2- to 4-hour intervals, and administer regular insulin every 4-6 hours as needed to maintain the plasma glucose level in the range of 100-250 mg/dL (ie, 5.55-13.88 mmol/L). Continue until the patient can be switched to oral feedings and a 2- or 3-dose insulin schedule. Some physicians prefer to withhold subcutaneous insulin on the day of the operation and to add 6-10 units of regular insulin to 1 L of 5% glucose in normal saline or water infused at 150 mL/h on the morning of the operation, depending on the plasma glucose level. The infusion is continued through recovery, with insulin adjustments depending on the plasma glucose levels obtained in the recovery room and at 2- to 4-hour intervals thereafter. Postoperative IV insulin infusion after major surgical procedures is currently considered the standard of care in most hospitals.

Glycemic Control During Pregnancy

Because pregnant patients with type 1 DM are at risk for multiple poor maternal and fetal outcomes, it is essential to provide these patients with prepregnancy counseling, good glycemic control before and during pregnancy, and a complete medical evaluation. (See Diabetes Mellitus and Pregnancy.) High-risk possibilities include exacerbation of existing hypertension, renal insufficiency, retinopathy, and more frequent congenital anomalies. These patients should be referred to obstetricians specializing in high-risk pregnancies. Despite advanced age, multiparity, obesity, and social disadvantage, patients with type 2 DM were found to have better glycemic control, fewer large-for-gestational-age infants, fewer preterm deliveries, and fewer neonatal care admissions than patients with type 1 DM.[101] This finding suggests that better tools are needed to improve glycemic control in patients with type 1 DM.

Prevention
Significant improvements in the prediction of type 1 DM have led to several trials of prevention. These include the Diabetes Prevention TrialType 1 (DPT-1) in the United States and the European Nicotinamide Diabetes Intervention Trial (ENDIT) in Europe and North America. Both trials have reported disappointing results. In DPT-1, parenteral insulin failed to delay or prevent type 1 DM in subjects at elevated risk (as indicated by family history and the presence of islet cell antibodies). These subjects received low-dose subcutaneous Ultralente insulin twice daily, plus annual 4-day continuous IV infusions of insulin.[102] DPT-1 subjects who received oral insulin experienced considerable delays in the onset of diabetes, but once therapy was stopped, their rate of developing diabetes increased to a rate similar to that seen in the placebo group. [103] In the ENDIT study, nicotinamide (which prevents autoimmune diabetes in animal models) did not prevent or delay the clinical onset of diabetes in people with a first-degree family history of type 1 DM. Subjects in the treatment arm received oral modified-release nicotinamide in a dose of 1.2 g/m 2.[104]

Slowing progress of recent-onset type 1 DM

In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. However, a trial of antigen-based immunotherapy with 2 or 3 doses of glutamic acid decarboxylase formulated with aluminum hydroxide (GAD-alum) vaccine for 4-12 weeks in patients with newly diagnosed type 1 DM did not alter the course of loss of insulin secretion during the first year.[105]

A phase 3 trial using an anti-CD3 monoclonal antibody, teplizumab, found an encouraging trend toward preservation of beta-cell function with reduction in daily insulin requirements in patients with recently diagnosed type 1 DM. However, rash was almost 3 times more common in treated patients than in those receiving placebo.[106] A study by Orban et al found that costimulation modulation of activated T cells with abatacept slowed reduction in beta-cell function over a 2-year period of administration. However, this effect was reduced after 6 months of treatment, suggesting that T-cell activation lessens over time. Further studies are needed. [107]

Consultations
Patients with type 1 DM should be referred to an endocrinologist for multidisciplinary management. They should also undergo a complete retinal examination by an ophthalmologist at least once a year. Those patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist. Patients with significant foot involvement should see a podiatrist.

Medication Summary
Insulin injected subcutaneously is the first-line treatment of type 1 diabetes mellitus (DM). The different types of insulin vary with respect to onset and duration of action. Short-, intermediate-, and long-acting insulins are available. Short-acting and rapid-acting insulins are the only types that can be administered intravenously (IV). Human insulin currently is the only species of insulin available in the United States; it is less antigenic than the previously used animal-derived varieties.

Antidiabetics, Insulins
Class Summary
Rapid-acting insulins are used whenever a rapid onset and short duration are appropriate (eg, before meals or when the blood glucose level exceeds target and a correction dose is needed). Rapid-acting insulins are associated with less hypoglycemia than regular insulin. Currently, short-acting insulins are less commonly used than the rapid-acting insulins in patients with type 1 DM. They are used when a slightly slower onset of action or a greater duration of action is desired. Intermediate-acting insulins have a relatively slow onset of action and a relatively long duration of action. They are usually combined with faster-acting insulins to maximize the benefits of a single injection. Long-acting insulins have a very long duration of action and, when combined with faster-acting insulins, provide better glucose control for some patients. In patients with type 1 DM, they must be used in conjunction with a rapidacting or short-acting insulin given before meals. Premixed insulins contain a fixed ratio of rapid-acting insulins with longer-acting insulin, which can restrict their use. Premixed insulin is usually not recommended in type 1 DM patients, because of their need for frequent adjustments of premeal insulin doses.
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Insulin aspart (NovoLog)

Insulin aspart has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours. Insulin aspart is approved by the US Food and Drug Administration (FDA) for use in insulin pumps.
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Insulin glulisine (Apidra)

Insulin glulisine has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours. Insulin glulisine is FDA-approved for use in insulin pumps.
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Insulin lispro (Humalog)

Insulin lispro has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours.
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Regular insulin (Humulin R, Novolin R)

Regular insulin has a short onset of action, 0.5 hour. Its peak effect occurs within 2-4 hours, and its usual duration of action is 5-8 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) insulin and 30% regular human insulin (eg, Novolin 70/30 and Humulin 70/30) are available, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use.
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Insulin detemir (Levemir)

Insulin detemir is indicated for once-daily or twice-daily subcutaneous administration in individuals with type 1 DM who require long-acting basal insulin for hyperglycemia control. Its duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). The prolonged action results from slow systemic absorption of detemir molecules from the injection site. Its primary activity is regulation of glucose metabolism. Insulin detemir binds to insulin receptors and lowers blood glucose levels by facilitating cellular uptake of glucose into skeletal muscle and fat; it also inhibits glucose output from the liver. The drug inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.
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Insulin glargine (Lantus)

Insulin glargine stimulates proper utilization of glucose by the cells and reduces blood sugar levels. It has no pronounced peaks of action, because a small amount of insulin is gradually released at a constant rate over 24 hours. A possible association of insulin glargine with an increased risk of cancer has been reported.
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Insulin aspart protamine/insulin aspart (NovoLog 70/30)

The combination of insulin aspart protamine with insulin aspart includes 30% rapid-onset insulin (ie, insulin aspart) and 70% intermediate-acting insulin (ie, insulin aspart protamine). Insulin aspart is absorbed more rapidly than regular human insulin, and insulin aspart protamine has a prolonged absorption profile after injection.
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Insulin lispro protamine/insulin lispro (Humalog 75/25)

The combination of insulin lispro protamine with insulin lispro includes 75% insulin lispro protamine, which has a prolonged duration of action, and 25% insulin lispro, which is a rapid-onset insulin.

Antidiabetics, Amylinomimetics
Class Summary
These amylinomimetic agents elicit endogenous amylin effects by delaying gastric emptying, decreasing postprandial glucagon release, and modulating appetite.
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Pramlintide acetate (Symlin)

Pramlintide acetate is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells that is deficient in people with type 1 DM. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation.

Hypoglycemia Antidotes
Class Summary
Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Glucagon increases blood glucose levels by promoting hepatic glycogenolysis and gluconeogenesis.
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Glucagon (GlucaGen)
Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). It increases hydrolysis of glycogen to glucose in the liver and accelerates hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract.

Etiopathogenesis of type 1 diabetes mellitus: prognostic factors for the evolution of residual cell function
Sergio A Dib1* and Marilia B Gomes2

*Corresponding author: Sergio A Dib sergio.dib@unifesp.br Author Affiliations

1 2

Endocrinology Division, Department of Medicine of Federal University of So Paulo, SP, Brazil Diabetes Division, Department of Medicine of State University of Rio de Janeiro, GB, Brazil

For all author emails, please log on. Diabetology & Metabolic Syndrome 2009, 1:25 doi:10.1186/1758-5996-1-25

The electronic version of this article is the complete one and can be found online at:http://www.dmsjournal.com/content/1/1/25

Received: Accepted: Published:

10 July 2009 4 December 2009 4 December 2009

2009 Dib and Gomes; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Type 1A diabetes mellitus (T1ADM) is a progressive autoimmune disease mediated by T lymphocytes with destruction of beta cells. Up to now, we do not have precise methods to assess the beta cell mass, "in vivo" or "ex-vivo". The studies about its genetic susceptibility show strong association with class II antigens of the HLA system (particularly DQ). Others genetics associations are weaker and depend on the population studied. A combination of precipitating events may occur at the beginning of the disease. There is a silent loss of immune-mediated beta cells mass which velocity has an inverse relation with the age, but it is influenced by genetic and metabolic factors. We can predict the development of the disease primarily through the determination of four biochemically islet auto antibodies against antigens like insulin, GAD65, IA2 and Znt8. Beta cell destruction is chronically progressive but at clinical diagnosis of the disease a reserve of these cells still functioning. The goal of secondary disease prevention is halt the autoimmune attack on beta cells by redirecting or dampening the immune system. It is remains one of the foremost therapeutic goals in the T1ADM. Glycemic intensive control and immunotherapeutic agents may preserve beta-cell function in newly diagnosed patients with T1ADM. It may be assessed through C-peptide values, which are important for glycemic stability and for the prevention of chronic complications of this disease. This article will summarize the etiopathogenesis mechanisms of this disease and the factors can influence on residual C-peptide and the strategies to it preservation.

Review
We are presently going through a revaluation of the knowledge acquired in the last decades regarding the etiopathogenesis of type 1 diabetes mellitus (T1DM).

Type 1 diabetes classification

Nowadays, we may subdivide T1DM in three groups from the etiological point of view: autoimmune, idiopathic and double. The autoimmune group is represented by: type 1A, which is polygenic and it is the most frequent type of this disease, corresponding to approximately 80-90% of all T1DM cases [1]. The other subtype of this group is the latent autoimmune diabetes in adults (LADA)[2], which appears after the age of 35 and is frequently associated with other autoimmune endocrine diseases. The third subtype includes called "monogenic" T1DM. They correspond to T1DM of the autoimmune polyglandular syndrome type 1A [3] and of IPEX syndrome (Immune Dysfunction, Polyendocrinopathy, Enteropathy, X-linked) [4].

Type 1B, also called idiopathic, has all the clinical features of type 1A, but the autoimmune component is not detected [5]. Another 1B subtype is the fulminant diabetes most described in Asian peoples, mainly Japan, China and Korea, characterized by a short clinical history, before to the first acute metabolic decompensation, presents the impairment of beta and alpha cells of the pancreatic islet and no autoimmune etiology [6]. Finally, the denomination of mixed, 1.5 or double (type 1 plus type 2) diabetes has been proposed when we have the type 1A (autoimmunity) plus type 2 (obesity, insulin resistance, dyslipidemia) diabetes characteristics in the same individual [7]. In this review, we will cover only autoimmune type 1A diabetes.

Type 1 A diabetes
Type 1 A diabetes is a chronic inflammatory disease which leads to selective destruction of beta cells in pancreatic islets [8]. Such cells are affected by a process involving specific cellular and humoral autoimmunity mechanisms against their antigens. A failure of regulatory T cells (T- regs) on this process is involved [9]. However, even though type 1 A diabetes is one of the most widely studied autoimmune diseases over the last decades, its complete natural history has not been fully clarified yet. One of the subtypes of type 1A diabetes is the "monogenic" diabetes, associated with the Autoimmune Polyglandular Syndrome Type 1 [10]. Such syndrome, also as APECED (Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy) is more frequent in children and pre-puberal individuals and is associated with the mutation of the autoimmune regulatory gene (AIRE), located in chromosome 21, that it is important to the regulation of autoimmune mechanisms [3]. A change in this gen results in autoimmune reactions to different antigens expressed in peripheral tissues due to a failure in regulating the presentation of such antigens in the thymus for its recognition as "self-antigens". As it is already known, a large part of autoimmune regulation occurs at the thymus level, so that when peripheral lymphocytes go through the thymus, they receive information about antigens to which they must react or not. When the individual suffers change in the AIRE gene, the selection criteria fail and these patients start to react against antigens to which they should not react. Type 1 diabetes is observed in 13-20% of these patients. They are generally referred by other specialists, because the first clinical manifestation, most of the times, is not hyperglycemia. The most frequent manifestations of this syndrome are mucocutaneous candidiasis, Addison's Disease and hypoparathyroidism [3]. It is interesting that in such patients, the glutamic acid decarboxylase antibodies (GADA), that in classical type 1A diabetes indicate pancreatic cell lesion, are more related to the presence of enteropathy [3]. The second "monogenic" subtype of type 1 A diabetes is a rare type of diabetes which occurs in children and is associated with changes in genes located in chromosome X [11]. In this type of diabetes, children present mutation in the gene which codifies the express of FOX-P3 in CD4+ and CD25+ cells. Such changes lead to a disability of generating regulatory T cells and the development of early autoimmunity against several organs. Thus, it is characterized by the onset of a different type of diabetes, dependent on exogenous insulin, enteropathy, growth deficiency and early death in such children [4]. Nevertheless, the polygenic group type 1 A diabetes is the most frequent form of T1DM and it is accountable for approximately 90% of these cases.

Genetic Predisposition
Type 1 A diabetes is considered by some authors a polygenic and by others, an oligogenic, but heterogeneous disease. To date, several loci in different chromosomes are related to the genetic susceptibility of this type of diabetes [12]. Such locis are denominated IDDM1, IDDM2, IIDM3, etc. Many of these loci are also related to the predisposition to other autoimmune diseases, such as multiple sclerosis, celiac disease, ankylosing spondylitis and Hashimoto's thyroiditis. The most important genes are located inside the major complex of histocompatibilty (MHC) in the region of class II of the HLA system, particularly molecules DR, DQ and DP in chromosome 6p21.31 [13]. These are called IDDM1 and are responsible for about 45% of the genetic susceptibility of type 1 A diabetes. Most of these data come from Caucasian populations from Europe and North-America. In these studies, approximately 95% of patients have class II antigens HLADR3 or - DR4 and 55 - 60% of them are heterozygotes DR3/DR4. Genotype DR3/DR4 offers higher risk for type 1 A diabetes, with a synergic mode of action, followed by homozygote DR4 or DR3, respectively. The data suggest that DR4 may offer this susceptibility in a dominant manner, while DR3 as a recessive feature. The latest studies using molecular biology techniques have demonstrated that the locus HLA-DQ is more narrowly associated with the susceptibility to type 1 A diabetes. Such locus codifies important proteins at the presentation and recognition of antigens by the immune system. In Caucasians, the heterodimers HLA-DQ (alpha chains denominated DQA1 and beta chains, DQB1) codified by the alleles DQA1*0301, DQB1*0302 and DQA1*0501, DQB1*0201 have the strongest association with type 1 A diabetes and are respectively not balanced at the connection to alleles HLADR4 and DR3. On the other hand, among four common DR2 haplotypes, observed in Caucasians, DQA1*0102, DQB1*0602, DRB1*1501 are negatively associated with type 1 A diabetes and are related in less than 1% of the majority of populations studied, including Asians, Afro-Americans and Mexican-Americans. This protection seems to have a dominant effect, as the presence of DQB1*0602 protects from diabetes, with rare exceptions, even in the concomitance of alleles of the HLA system of high risk of the disease. In other ethnical groups, the susceptibility for type 1 A diabetes associated with the genes of the HLA system may involve other alleles. Particularly in Brazil, the latest studies in populations of the Northeast [14] and Southeast[15] show higher frequency of antigens DRB1*03 and DRB1*04 in type 1 diabetes than in normal controls. One of the genes related to the protection is DRB1*11 in both Brazilian populations studied [14,15]. For nearly 20 years, Bell et al[16] found out that variations in the number of nucleotide elements repeated (Variable Number of Tanden Repeats - VNTR) of the 5' portion of the insulin gene were associated with the development of type 1 A diabetes. A longer group of repetitions was associated with a reduced risk of diabetes. Such studies have been replicated and have demonstrated that the important locus is clearly limited to the insulin gene [17]. It is denominated IDDM2, located in chromosome 11p15.5 and contributes with approximately 10% of this disease susceptibility. One of the mechanisms

suggested for the susceptibility and resistance associated with IDDM2 is related to the influence of VNTR in the transcription of insulin in the thymus, necessary to establish self-tolerance during body growth and development. In a third place of this disease prediction is a lymphocyte specific phosphatase (PTPN22) gene[18]. Another locus associated with a modulation of the immune response and with type 1 A diabetes, in some populations, is IDDM12 in chromosome 2q33, related to a protein 4 of cytotoxic T lymphocytes (CTLA-4)[19]. In summary, IDDM1 and IDDM2 compete to approximately 50% of the family aggregation of type1 A diabetes. The remaining 50% probably occur due to additional inherited polymorphisms/mutations. The lack of 100% concordance in identical twins could be due to somatic mutations, gene rearrangements by chance (e.g., rearrangements in T cell receptors) or to environmental factors. Ultimately, it is important to emphasize that genes may have unique behavior among autoimmune diseases, where a group is related to susceptibility and another is related to a significant protection and, many times, surpassing susceptibility. Studies using recent techniques for identifying genes and the formation of cooperative study groups must increase the speed of appearance of susceptibility genes for type 1 A diabetes.

Environmental Factors
The incidence of type 1A diabetes has increased dramatically in many countries during the past four decades; it is likely that some factors in the environment are changing. Several environmental factors have already been associated with the development of type 1 A diabetes, such as viruses, certain constituents of diet and preservatives food. The gastrointestinal tract is likely the main system through which non-self antigens gain access. Recent data from literature have emphasized the importance of the intestinal barrier, which is an entry door for viruses and proteins. In early childhood, such barrier is immature, which allows the passage of several antigens, and when these antigens are presented to T lymphocytes by the antigen presenting cells (macrophages), they will trigger an immune response which might result in a autoimmune process. Fasano A et al [20,21] have recently reported a novel protein, zonulin, that modulates intestinal permeability by disassembling the intercellular tight junctions. Such protein may be assessed in the plasma and studies demonstrate that its serum concentration is increased in patients with type 1 A diabetes in relation to their relatives and to controls[22], suggesting that a possible link between genetic susceptibility, increased intestinal permeability, environmental exposure to non-self antigens and development of autoimmune disease. The influence of several environmental factors in the development of type 1 A diabetes, such as birth-related factors (type of birth, new-born weight), infections, vaccinations, diet components and psychosocial factors are being assessed in a longitudinal study with children since their first months of life up to the age of 15 (TEDDY study). People interested in such study may enroll through the electronic address http://Teddy.epi.usf.edu/TEDDY/index.htm webcite.

Autoimmune Process
The selective destruction of beta cells of pancreatic islets in T1ADM is the result of a complex interrelation among beta cells, the immune system and environmental factors in individuals genetically susceptible. However, the mechanisms which start the changes in this interrelation and lead to the development of T1DM are not yet fully clarified and, up to now, there are no specific genes or proteins for most of the cases of T1ADM. Proteins are involved in most cellular processes and the cumulative expression of certain proteins may reflect the specific activities of these cells, thus proteomics may be useful to describe the protein profile expression of cells and of their diabetic phenotype. In this sense, the study of proteomics and metabolomics is an area which seeks the development of methods able to characterize, through biologic samples, bioindicators able to diagnose diseases in initial stage, to predict levels of susceptibility and to monitor the disease progression and its response to therapies. Proteomics has been applied in studies of beta cell differentiation, exposure of islets to cytokines, manipulation of the nutritional pattern of islets and of transplanted cells. Though these studies have revealed a complex and detailed scene of the protein expression profiles of these cells, their functional implications have not been clarified yet. Up to now, data indicate that beta cells participate actively in their self-destruction during the development of T1DM. Likewise, it seems that there is not any isolated protein responsible for the disease development, but there are serial reactions which favor the transition of dynamic stability of healthy beta cells to dynamic instability and eventual destruction of beta cells [23]. Considering the above mentioned, we may infer that the T1DM prevention is difficult. It is supposed that, in the autoimmune process evolution, individuals produce different proteins, antigens with the expression of different epitopes which were not detected initially, contributing to the process perpetuation. According to the suggestion of a recent article[24] in the beginning of the autoimmune process against pancreatic beta cells, we may have three or more antigens, but at the end, there are endless antigens which are activating the process, i.e., the greater the beta cell lesion, the more antigens are expressed, which will reactivate the process. This proposal covers a new concept for the natural history of T1ADM which, in its preclinical stage, would be characterized by a succession of relapses and remissions with interrelation between regulatory T cells (T-regs) and effectors cells, and regeneration of beta cells up to the moment when the percentage of beta cell destruction would no longer allow a proper insulin secretion, resulting in the expression of hyperglycemia. Within this context, it becomes important to mention the low capacity of regeneration/neogenesis of beta cells mainly when they are exposed to hyperglycemia, which is a stimulus metabolic factor to the insulin secretion, but it is also glycotoxic. When proper glycemic control is instituted at the beginning of the disease, these cells have acquiescence and may to keep the levels of C-peptide secretion for a additional period of time.

After presenting the antigen by the macrophages to T lymphocytes, at least four types of answer may be induced in the immune system: Th1 (cellular immune response), Th2 (humoral immune response), Th17 (cellular immune response potentialization) and T-regs (which take the control of immune cellular reactions). Nowadays, T1DM is considered a T- reg disease, both by its decrease or by its function alteration (e.g., T lymphocytes of Th1 response with Th17 which do not obey the regulation of T- reg cells). This was confirmed by the publication of T1DM cases in individuals who did not produce antibodies through congenital agamaglobulinemia [25,26]. In such individuals, the Th2 response was absent and thus there was no antibody production. At the same time, it is also known that during the pathogenetic process, peripancreatic T lymphocytes play an important role in the transmission of local reactions in islets to systemic cells [27]. The anti-islet antibodies circulating also express the inflammatory lesion taking place in the pancreas. In T1ADM the most studies autoantibodies are classical anti-islet (evaluated through the indirect immunofluorescence method and using as substract cry preserved human pancreas sections), glutamic acid decarboxylase antibodies (GADA), anti-tyrosine-phosphatase (IA2/ICA512) antibodies and anti-insulin autoantibodies. The presence of autoimmunity against the pancreatic islets is considered when the individual has one or more antibodies persistent for at least 3 to 6 months. It is important to confirm these antibodies at least two times in three different occasions. Antigens ICA512 (IA-2) and later IA-2 (fogrin-phosphatase of insulinoma granules) were isolated independently by different investigators [28-30]. Almost all antibodies which react with IA-2 also react with IA-2, while approximately 10% of patients who develop T1ADM have antibodies reacting against IA2, but not IA-2. Thus, during the routine, the IA-2 essay is unnecessary. So far, insulin and pro-insulin are the only specific antigens of beta cells (all the other antigens described can also to be founded at other cells). The insulin molecule epitope recognized by the liquid phase essays seems to be homogeneous [31]. The anti-insulin antibodies react with conformational molecule epitope (not against chains A or B separately) [32]. Nowadays, studies has been shown that this epitope is between the positions 23 and 30 in the insulin beta chain. Essays for anti-insulin antibodies have more specificity for the disease than the ones against proinsulin. Anti-insulin antibody values correlate inversely with the age when T1ADM develops. Thus, values above 2000 nU/ml are almost exclusively present in children who develop this disease before the age of 5 and less than 50% of the individuals who develop T1ADM after the age of 15 years old may have these autoantibodies. Such antibody value is, to some degree, genetically determined and associated with DR4 [33], DQ8 [32], DQA1*0102, 0201,0301, 0401[33]. There are data suggesting that the anti-insulin antibody value among individuals with positive ICA is inversally related to time of their evolution to the clinical disease [34]. Usually, antiinsulin antibodies are the first to appear in children who develop T1DM [34-36], mainly in children below 1 year of age. From five children with early (around 8 months old) high anti-insulin antibodies titers, 4 developed T1ADM below the age of 3 years old [35]. Among T1ADM relatives children who are persistently positive only to anti-insulin antibodies rarely develop clinical T1DM [33], but a high percentage of those who show another anti-islet cell antibody evolve to T1ADM after 10 years of age. Adolescents and adults present low concentration of anti-insulin antibodies. The use of vaccines constituted from fragments 9-23 of the insulin B chain, as recently performed with GAD-65, has been tested in experimental T1ADM models to verify their immunomodulate power in the natural history of the disease [37]. The last of antigens described in the autoimmune process against pancreatic beta cells was one of the bivalent cation (zinc) transporters [38]. Such antigen was characterized through the microarray technique and showed specificity of approximately 80% and high clonal pancreatic frequency. When this new antibody were analyzed together the antibodies previously described (GADA, anti-insulin and anti-IA2), it was possible to increase the autoimmune T1DM diagnosis from 80-85% to 98.2%. The analysis concerning the evolution profiles of individuals with multiple anti-islet autoantibodies was assessed in the DAISY study [39]. In this study where children are assessed consecutively since birth regarding these autoantibodies and glucose tolerance, it was possible to characterize three evolution profiles: 1- Positive transitory (individuals transitorily positive for antibodies who do not develop the disease); 2- Non-diabetics (individuals persistently positive for autoantibodies who do not develop the disease) and 3- Pre-diabetics (individuals persistently positive for multiple autoantibodies who develop the disease). The beta cell recovery function after the clinical diagnosis of the disease is extremely rare. One report [40], a few years ago, shown a patient (male, 13 years old) with a classical T1DM(low C-peptide secretion, DQB1*0303,0501), that was initially treated with insulin but it was discontinued after eleven months. Four years after de clinical diagnosis the reevaluation of this patient showed an improvement in the C-peptide secretion and normal glucose tolerance. The immunological assessment showed that GADA were initially positive, but the concentration was low ( 10 U/ml), persisting weakly positive ( 2 U/ml) and anti-insulin and IA2 autoantibodies which were initially positive became negative later. At the same time, the lymphocyte response to proinsulin showed elevated concentration of interleukin 10, which is one of the protective interleukins for the autoimmune T1DM process and trophy for Treg cells, demonstrating the important role of these cells in the process. However, this patient evolution is an exception, as in most cases there is a progressive decline in C-peptide secretion during the natural history of this disease, following the start of glycemic instability. In our experience, approximately 60% of T1DM with less than 6 months of clinical diagnosis present residual C-peptide secretion (baseline > 0.6 ng/ml) but which presents a significant drop after 2 to 3 three years of diagnosis and only 3% of individuals over 5 years of diagnosis present positive C-peptide secretion.

Preservation of the residual C-peptide secretion

Today, one of the therapeutic goals in T1DM is the preservation of the residual C-peptide secretion that is detected in a significant percentage of patients at diagnosis and which potentially may influence the clinical course of the disease.

Several studies have been demonstrated that residual C-peptide secretion, after T1ADM diagnosis, depends on genetic factors, the patient's age at the diabetes diagnosis, the number of anti-islet antibodies and the residual C-peptide secretion. At the same way, intensive insulin therapy and immunomodulators drugs may be useful in this direction. Regarding genetic factors, the first ones studied were from the HLA system. Among these, A24 +DQA1+03+ and DR9+ have been associated to a higher velocity of C-peptide levels decrease. Patients who do not have these genes would keep a better beta cell function and higher C-peptide secretion [41]. Two other genetic factors related to residual C-peptide secretion are PTPN-P22 (protein tyrosine phosphatase non-receptor type 2[42] and one of the vitamin D receptor polymorphism (Fok1)[43]. PTPN22 gene codifies a lymphoid specific phosphatase synthesis, known as LYP, which is important to inhibit T lymphocites activation. A change in the LYP function leads to an alteration in regulatory T cells CD4+CD25+, making the system less powerful to suppress immune response against autoantigens. The residual C-peptide secretion follow-up on the first 12 months of the disease in T1DM patients showed that it decreased in patients who had alterations in such gene [42]. Among unconventional actions of this vitamin is its immunomodulating function [43]. In this way, we assess the relation of the frequency of one of vitamin D polymorphism receptor, FOK-1, in a group of T1DM with 7 years average period of diagnosis and we verified that the patients who had this polymorphism presented lower residual C-peptide secretion [44]. It is classically known that children and adolescents (0 to 17 years old) present at T1DM diagnosis a lower C-peptide response to a mixed meal than adults [45]. However, there are recent literature data which demonstrates that, despite this initially higher C-peptide reserve in adults, the dropping speed after diagnosis is similar in young patients [46]. Similar data we found in a univariated analysis study (with fasting C-peptide as depending variable) on a T1DM group, where we verified a positive correlation with the age of the patient at clinical diagnosis (r = 0.270; p = 0.001) and negative with the disease duration (r = -0.652; p < 0.001) and with the HbA1c value (r = -0.176; p = 0.029) of our population. So it was demonstrated that, apart from patients' age, disease duration as the exposure to hyperglycemia time are also important to the maintenance of residual C-peptide secretion. Another widely discussed aspect in literature is the ability of pancreatic beta cells to regenerate. In a recent case report, where it was possible to assess this factor in a pancreas sample from an 89-year-old patient, T1DM (GADA, IA2 positive and lower fasting C-peptide) of recent diagnosis, submitted to surgery to neo pancreatic duct. Duplicating beta cells were detected in the pancreatic tissue through immunohistochemical analysis and potassium channel indicators [47]. Such case study shows that a potential pancreatic beta cell regeneration is a possibility to be considered while we are discussing the residual C-peptide secretion in T1DM. The number of anti-islet auto-antibodies during the pre-diabetic stage and at diagnosis of T1DM shown a inverse relation with the residual beta cell [48]. This is easily verified when we compare T1DM in children and LADA [49]. At T1DM diagnosis, apart from the autoimmune insult, beta cells are being submitted to hyperglycemia itself by the glycotoxic effect, which also cooperates to decrease C-peptide secretion. This last effect could be demonstrated when a residual insulin secretion was compared in two groups of T1DM with the same clinical features during the first two years from clinical diagnosis, one submitted to intensive insulin therapy and other under conventional therapy [50]. In this study, it was observed that even through both groups present the same residual C-peptide secretion at diagnosis and after the 1st followup year, by the end of the 2nd year it was significantly higher in the intensive therapy group. However, it has been discussed if such effect was obtained through the removal of glycotoxicity or through the insulin immunomodulate effect. Regarding immunomodulators, we evaluated nicotinamide in a double blind study during the 1styear of T1DM diagnosis. In this study although the fasting C-peptide did not change, we did not see any differences between patients who used this vitamin and placebo [51]. Since a few years ago, some studies have been conducted using as immunomodulators the antigens involved in the autoimmune process against beta cells. One of the first these clinical trials was a double-blind study, stage II which used a heat-shock protein peptide (Diapep27) [52]. In this study recently diagnosed T1DM patients received this peptide at their clinical diagnosis, and 1 to 6 months later. It was demonstrated that the group which received this vaccine presented significantly higher residual C-peptide secretion from the 7thmonth and this result was until the end of the study (10 th month), while in the placebo group, there was a progressive reduction in the fasting-C peptide since the 1st month of diagnosis. Another study in this way used monoclonal anti-CD3 [53] antibody, which was also able to cooperate to C-peptide preservation during the 1st year of diagnosis. The most recent study for the denominated "secondary prevention of T1DM" used vaccine with GAD-65[54]. In this study, recently diagnosed T1DM patients received 20 g GAD-alum on the 1stand 30th days of the protocol. It was demonstrated through this study, for patients who received this vaccine up to 6 months after clinical diagnosis, that the fasting C-peptide was significantly higher than the placebo group on the 10 th and 30th month of the study. The secondary prevention of T1DM has acquired increasing importance in the last few years due to the insufficiency of the latest large studies [54,55] for primary prevention and to the positive effect of the C-peptide residual secretion to prevent hypoglycemia[56] and the prevention of diabetic microangiopathy (nephropathy and neuropathy)[57]. These last actions should be related to a higher stability of glycemia in these individuals and to possible actions which would be intermediated through the insulin receptor or a specific C-peptide receptor. Such "hormone" would supposedly act through G protein, C-peptide receptor and protein kinase C (PKC) and MAPK and nuclear transcription factors [58]. Renal, circulatory and neural clinical actions have been related to the C-peptide [59].

Conclusion
In short, T1DM is a progressive autoimmune disease mediated by T cells with destruction of beta cells. Up to now, we do not have precise methods to assess the beta cell mass, "in vivo" or "ex-vivo". The studies about its genetic susceptibility show strong association with class II antigens of the HLA system (particularly DQ). Other associations are weaker and depend on the studied population. A combination of precipitating events (virus, food factors and others) must occur at the beginning of the disease, and the intestinal barrier must play an important role in this process. There is a silent loss (immunomediated) of the beta cells mass which velocity has an inverse relation with the age, but it is influenced by genetic and metabolic factors. However, in the clinical diagnosis of the disease, there is a significant reserve of functioning beta cells. The goal of secondary prevention, by the immunomodulation of the process, is the preservation of such functional beta-cell reserve. It may be assessed through C-peptide values, which are important for glycemia stability and for the prevention of chronic complications in this disease. However, the determinant risk factors of T1ADM, the autoimmune response initiators, the mechanisms which regulate the process toward beta cell failure and the factors which determine the time of clinical diabetes arrive are not fully known yet.

Abbreviations
T1DM: type 1 diabetes mellitus; T1ADM: type 1A diabetes mellitus; LADA: latent autoimmune diabetes in adults; IPEX: immune dysfunction, polyendocrinopathy, enteropathy X-linked; T-regs: regulatory T cells; APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AIRE: autoimmune regulatory gene; GADA: glutamic acid decarboxilase antibodies; MHC: major complexo of histocompatibility; VNTR: variable number of tanden repeats; TEDDY: The Environmental Determinants of Diabetes in the Young; Th1: immune cellular response; Th2: immune humoral response; DAISY: Diabetes Autoimmunity Study in the Young; PTPN-22: protein tyrosine phosphotase non-receptor type 2; PKC: protein kinase C; MAPK: mitogen-activated protein kinase.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
SAD wrote and MBG reviewed this manuscript. Both authors read and approved the final manuscript

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