Definition and diagnostic criteria for diabetes mellitus and other categories of glucose intolerance

2.1 Definition
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and
protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include longterm damage, dysfunction and
failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe
forms, ketoacidosis or a nonketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death. Often symptoms are
not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the
diagnosis is made. The longterm effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness,
nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including
sexual dysfunction. People with diabetes are at increased risk of Cardiovascular, peripheral vascular and cerebrovascular disease. Several pathogenetic processes
are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others
that result in resistance to insulin action. The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues
resulting from insensitivity or lack of insulin.

Diabetes in children
Diabetes in children usually presents with severe symptoms,very high blood glucose levels, marked glycosuria, and ketonuria. In most children the diagnosis is
confirmed without delay by blood glucose measurements, and treatment (including insulin injection) is initiated immediately, often as a lifesaving measure. An
OGTT is neither necessary nor appropriate for diagnosis in such circumstances. A small proportion of children and adolescents, however, present with less severe
symptoms and may require fasting blood glucose measurement and/or an OGTT for diagnosis.

Diagnostic criteria
The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine volume,recurrent infections, unexplained weight loss and, in
severe cases, drowsiness and coma; high levels of glycosuria are usually present. For clinical purposes, an OGTT to establish diagnostic status need only be
considered if casual blood glucose values lie in the uncertain range (i.e. between the levels that establish or exclude diabetes) and fasting blood glucose levels are
below those which establish the diagnosis of diabetes. If an OGTT is performed, it is sufficient to measure the blood glucose values while fasting and at 2 hours after
a 75 g oral glucose load. For children the oral glucose load is related to body weight: 1.75 g per kg. The diagnostic criteria in children are the same as for adults.

Classification
Diabetes mellitus is classified into four broad categories: type 1, type 2, gestational diabetes, and "other specific types". The "other specific types" are a collection of
a few dozen individual causes. The term "diabetes", without qualification, usually refers to diabetes mellitus. The rare disease diabetes insipidus has similar
symptoms to diabetes mellitus, but without disturbances in the sugar metabolism and does not involve the same disease mechanisms.
The term "type 1 diabetes" has replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes mellitus
(IDDM). Likewise, the term "type 2 diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and noninsulin-dependent
diabetes mellitus (NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature.

Type 1 diabetes
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to insulin deficiency. This type
can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which beta cell loss is a T-cell-
mediated autoimmune attack. There is no known preventive measure against type 1 diabetes, which causes approximately 10% of diabetes mellitus cases in North
America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually
normal, especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed "juvenile diabetes" because a majority of these
diabetes cases were in children.
"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe the dramatic and recurrent swings
in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used. There are
many reasons for type 1 diabetes to be accompanied by irregular and unpredictable hyperglycemia, frequently with ketosis, and sometimes serious hypoglycemia,
including an impaired counterregulatory response to hypoglycemia, occult infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and
endocrinopathies (e.g., Addison's disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.

Type 2 diabetes
Type 2 diabetes mellitus is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion.
[2]
The defective responsiveness of
body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are
classified separately. Type 2 diabetes is the most common type.
In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage, hyperglycemia can be reversed by a variety of measures
and medications that improve insulin sensitivity or reduce glucose production by the liver.
Gestational diabetes
Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and
responsiveness. It occurs in about 25% of all pregnancies and may improve or disappear after delivery. Gestational diabetes is fully treatable, but requires careful
medical supervision throughout the pregnancy. About 2050% of affected women develop type 2 diabetes later in life.
Though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight),
congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and
cause respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as
a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A Caesarean section may be
performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.
A 2008 study completed in the U.S. found the number of American women entering pregnancy with pre-existing diabetes is increasing. In fact, the rate of diabetes
in expectant mothers had more than doubled from 1999 to 2005. This is particularly problematic as diabetes raises the risk of complications during pregnancy and
increases the potential for the children of diabetic mothers to become diabetic in the future.

SIGNS AND SYMPTOMS
The classic symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst), and polyphagia(increased hunger). Symptoms may
develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.
Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common
complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.
Diabetic emergencies
People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a
rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.
A rare but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration.

Complications
All forms of diabetes increase the risk of long-term complications. These typically develop after many years (1020), but may be the first symptom in those who
have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood. Diabetes doubles the risk
of cardiovascular disease. The main "macrovascular" diseases (related to atherosclerosis of larger arteries) are coronary artery
disease (angina andmyocardial infarction), stroke, and peripheral vascular disease. About 75% of deaths in diabetics are due to coronary artery disease.
Diabetes also damages the capillaries (causes microangiopathy). Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to
visual symptoms including reduced vision and potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes
in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis.
Another risk is diabetic neuropathy, the impact of diabetes on the nervous system most commonly causing numbness, tingling, and pain in the feet, and also
increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot
problems (such as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation. Additionally, proximal diabetic neuropathy causes
painful muscle wasting and weakness.
Several studies suggest a link between cognitive deficit and diabetes. Compared to those without diabetes, the research showed that those with the disease have a
1.2 to 1.5-fold greater rate of decline in cognitive function, and are at greater risk.
In the United States, there were approximately 675,000 diabetes-related emergency department (ED) visits in 2010 that involved neurological complications,
409,000 ED visits with kidney complications, and 186,000 ED visits with eye complications.
Causes
The cause of diabetes depends on the type.
Type 1
Type 1 diabetes is partly inherited, and then triggered by certain infections, with some evidence pointing at Coxsackie B4 virus. A genetic element in individual
susceptibility to some of these triggers has been traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system).
However, even in those who have inherited the susceptibility, type 1 DM seems to require an environmental trigger. The onset of type 1 diabetes is unrelated to
lifestyle.
Type 2
Type 2 diabetes is due primarily to lifestyle factors and genetics. A number of lifestyle factors are known to be important to the development of type 2 diabetes,
including obesity (defined by abody mass index of greater than thirty), lack of physical activity, poor diet, stress, and urbanization. Excess body fat is associated
with 30% of cases in those of Chinese and Japanese descent, 60-80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific
Islanders. Those who are not obese often have a high waisthip ratio.
Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-sweetened drinks in excess is associated with an increased risk. The
type of fats in the diet is also important, with saturated fats and trans fatty acids increasing the risk and polyunsaturated and monounsaturated fat decreasing
the risk. Eating lots of white rice appears to also play a role in increasing risk. A lack of exercise is believed to cause 7% of cases.
The following is a comprehensive list of other causes of diabetes:
Genetic defects of -cell function
Maturity onset diabetes of the young
Mitochondrial DNA mutations
Genetic defects in insulin processing or insulin action
Defects in proinsulin conversion
Insulin gene mutations
Insulin receptor mutations
Exocrine pancreatic defects
Chronic pancreatitis
Pancreatectomy
Pancreatic neoplasia
Cystic fibrosis
Hemochromatosis
Fibrocalculous pancreatopathy
Endocrinopathies
Growth hormone excess (acromegaly)
Cushing syndrome
Hyperthyroidism
Pheochromocytoma
Glucagonoma
Infections
Cytomegalovirus infection
Coxsackievirus B
Drugs
Glucocorticoids
Thyroid hormone
-adrenergic agonists
Statins
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PATHOPHYSIOLOGY


The fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day with three meals - one of the effects of a sugar-rich vs
a starch-rich meal is highlighted.


Mechanism of insulin release in normal pancreatic beta cells - insulin production is more or less constant within the beta cells. Its release is triggered by food, chiefly
food containing absorbable glucose.
Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system
cells). Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.
Humans are capable of digesting some carbohydrates, in particular those most common in food; starch, and some disaccharides such as sucrose, are converted
within a few hours to simpler forms, most notably the monosaccharide glucose, the principal carbohydrate energy source used by the body. The rest are passed
on for processing by gut flora largely in the colon. Insulin is released into the blood by beta cells (-cells), found in the islets of Langerhans in the pancreas, in
response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as
fuel, for conversion to other needed molecules, or for storage.
Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in
the reduced release of insulin from the -cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the
hormone glucagon, which acts in the opposite manner to insulin. Glucose thus forcibly produced from internal liver cell stores (as glycogen) re-enters the
bloodstream; muscle cells lack the necessary export mechanism. Normally, liver cells do this when the level of insulin is low (which normally correlates with low
levels of blood glucose).
Higher insulin levels increase some anabolic ("building up") processes, such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is
the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low
insulin level is the trigger for entering or leaving ketosis (the fat-burning metabolic phase).
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective,
then glucose will not have its usual effect, so it will not be absorbed properly by those body cells that require it, nor wil l it be stored appropriately in the liver and
muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.
When the glucose concentration in the blood is raised to about 9-10 mmol/L (except certain conditions, such as pregnancy), beyond its renal threshold(i.e. when
glucose level surpasses the transport maximum of glucose reabsorption), reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the
glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased
urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments,
causing dehydration and increased thirst.

DIAGNOSIS

WHO diabetes diagnostic criteria
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 one of the following:
Fasting plasma glucose level 7.0 mmol/l (126 mg/dl)
Plasma glucose 11.1 mmol/l (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test
Symptoms of hyperglycemia and casual plasma glucose 11.1 mmol/l (200 mg/dl)
Glycated hemoglobin (Hb A1C) 6.5%.
A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above methods on a different day. I t is preferable 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 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.
Per the World Health Organization people with fasting glucose levels from 6.1 to 6.9 mmol/l (110 to 125 mg/dl) are considered to have impaired fasting
glucose. people with plasma glucose at or above 7.8 mmol/L (140 mg/dL), but not over 11.1 mmol/L (200 mg/dL), two hours after a 75 g oral glucose load are
considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes
mellitus, as well as cardiovascular disease. The American Diabetes Association since 2003 uses a slightly different range for impaired fasting glucose of 5.6 to
6.9 mmol/l (100 to 125 mg/dl).
Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.
Management
Main article: Diabetes management
Diabetes mellitus is a chronic disease, for which there is no known cure except in very specific situations. Management concentrates on keeping blood sugar levels
as close to normal ("euglycemia") as possible, without causing hypoglycemia. This can usually be accomplished with diet, exercise, and use of appropriate
medications (insulin in the case of type 1 diabetes; oral medications, as well as possibly insulin, in type 2 diabetes).
Patient education, understanding, and participation is vital, since the complications of diabetes are far less common and less severe in people who have well-
managed blood sugar levels. The goal of treatment is an HbA1C level of 6.5%, but should not be lower than that, and may be set higher. Attention is also paid to
other health problems that may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood
pressure, and lack of regular exercise. Specialised footwear is widely used to reduce the risk of ulceration, or re-ulceration, in at-risk diabetic feet. Evidence for
the efficacy of this remains equivocal, however.
Medications
See also: Anti-diabetic medication
Metformin is generally recommended as a first line treatment for type 2 diabetes, as there is good evidence that it decreases mortality. Routine use of aspirin,
however, has not been found to improve outcomes in uncomplicated diabetes.
Type 1 diabetes is typically treated with a combinations of regular and NPH insulin, or synthetic insulin analogs. When insulin is used in type 2 diabetes, a long-
acting formulation is usually added initially, while continuing oral medications. Doses of insulin are then increased to effect.
Globally, as of 2010, an estimated 285 million people had diabetes, with type 2 making up about 90% of the cases. In 2011 it resulted in 1.4 million deaths
worldwide making it the 8th leading cause of death. This is an increase from 1 million deaths in 2000.Its rate has increased, and by 2030, this number is estimated to
almost double. Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in more developed countries. The greatest increase in rates
is, however, expected to occur in Asia and Africa, where most people with diabetes will probably be found by 2030. The increase in rates in developing countries
follows the trend of urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an environmental (i.e., dietary) effect,
but there is little understanding of the mechanism(s) at present, though there is much speculation, some of it most compellingly presented.
Its rate has increased, and by 2030, this number is estimated to almost double. Diabetes mellitus occurs throughout the world, but is more common (especially
type 2) in more developed countries. The greatest increase in rates is, however, expected to occur in Asia and Africa, where most people with diabetes will probably
be found by 2030.
[42]
The increase in rates in developing countries follows the trend of urbanization and lifestyle changes, perhaps most important ly a "Western-
style" diet. This has suggested an environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is much
speculation, some of it most compellingly presented.

Almost in every family an individual has Diabetes. My Father is suffering from Diabetes Type 1. This can be hereditary as my grandfather had diabetes. All of my
fathers brothers have acquired Diabetes.