Diagnostic Considerations

Type 2 diabetes mellitus can usually be differentiated from type 1 diabetes mellitus on the basis of history and physical examination findings and simple laboratory tests. Correctly determining whether a patient has type 1 or type 2 diabetes is important because patients with type 1 diabetes are dependent on a continuous source of exogenous insulin and carbohydrates for survival. Patients with type 2 diabetes may not need treatment of hyperglycemia during periods of fasting or decreased oral intake. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 diabetes. 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 diabetes. When dealing with patients with known diabetes in the emergency department, distinguishing the type of diabetes can be difficult in 2 groups: patients who are treated with insulin and are young but clinically appear to have type 2 diabetes; and older patients with late onset of diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 diabetes. (This latter group is now said to have latent autoimmune diabetes of the adult [LADA]). When in doubt, the patient should be treated with insulin and his or her glucose levels should be closely monitored. Some adolescents or young adults, mostly Hispanic or African American patients, who present with classic DKA are subsequently found to have type 2 diabetes. Pre-diabetes

Pre-diabetes often precedes overt type 2 diabetes. Prediabetes is defined by a fasting blood glucose level of 100125 mg/dL or a 2-hour post oral glucose tolerance test (OGTT) glucose level of 140-200 mg/dL. Persons with prediabetes have an increased risk for macrovascular disease as well as diabetes.[32] Often confused with pre-diabetes is the metabolic syndrome (also called syndrome X or the insulin-resistance syndrome). Metabolic syndrome, thought to be due to insulin resistance, can occur in patients with overtly normal glucose tolerance, pre-diabetes, or diabetes. It is diagnosed when a patient has at least 3 of the following 5 conditions: Abdominal obesity Elevated triglyceride level Low HDL-C level Elevated blood pressure Fasting glucose value greater than or equal to 100 mg/dL Eventually, clinically apparent insulin resistance develops. Unfortunately, insulin resistance is not measured clinically, except in research settings. An elevated fasting blood glucose level is the first indication of insulin resistance, but fasting insulin levels are generally increased long before this occurs. Measurement of fasting insulin levels are not yet recommended for the diagnosis of insulin resistance. An effort to standardize insulin assays is under way and may allow for the use of fasting insulin levels to diagnose insulin resistance in the future.

Differentials

Diabetes Mellitus, Type 1 Insulin Resistance Obesity

Tests to Differentiate Type 2 and Type 1 Diabetes

Measuring concentrations of insulin or C-peptide (a fragment of proinsulin that serves as a marker for insulin secretion) rarely is necessary to diagnose type 2 diabetes mellitus or differentiate type 2 diabetes from type 1 diabetes mellitus. Insulin levels generally are high early in the course of type 2 diabetes mellitus and gradually wane over time. A fasting C-peptide level more than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes (ie, residual beta-cell function). Stimulated C-peptide concentrations (after a standard meal challenge such as Sustacal or after glucagon) are somewhat preserved until late in the course of type 2 diabetes mellitus. Absence of a C-peptide response to carbohydrate ingestion may indicate total beta-cell failure. Antibodies to insulin, islet cells, or glutamic acid decarboxylase (GAD) are absent in type 2 diabetes mellitus. Latent autoimmune diabetes of adults (LADA) is a form of slow-onset type 1 diabetes that occurs in middle-aged (usually white) adults. It can be differentiated from type 2 diabetes by measuring anti-GAD65 antibodies. Such patients may respond to insulin secretagogues for a brief period (months). Autoantibodies can be useful in differentiating between type 1 diabetes and type 2 diabetes. Islet-cell (IA2), anti-GAD65, and anti-insulin autoantibodies can be present in early type 1, but not type 2, diabetes. Measurements of islet-cell (IA2) autoantibodies within 6 months of diagnosis can help differentiate type 1 and type 2 diabetes. These titers decrease after 6 months. Anti-GAD65 antibodies are

suggestive of type 1 diabetes. They can be present at diagnosis and are persistently positive over time.

United States statistics

A 2011 Centers for Disease Control and Prevention (CDC) report estimates that nearly 26 million Americans have diabetes.[14] Additionally, an estimated 79 million Americans have prediabetes. Diabetes affects 8.3% of Americans of all ages and 11.3% of adults aged 20 years and older, according to the National Diabetes Fact Sheet for 2011. [14] About 27% of those with diabetes7 million Americans do not know they have the disease. Prediabetes affects 35% of adults aged 20 years and older. About 215,000 people younger 20 years had diabetes (type 1 or type 2) in the United States in 2010.[14] In 2008, the CDC estimated that 23.6 million Americans, or 7.8% of the population, had diabetes and another 57 million adults had prediabetes. Pre-diabetes, as defined by the American Diabetes Association, is that state in which blood glucose levels are higher than normal but not high enough to be diagnosed as diabetes. It is presumed that most persons with elevated glucose levels approaching the level needed for the diagnosis of diabetes will subsequently progress to diabetes. The 2001 estimates have increased because of the following reasons:[14]more people are developing diabetes, people with diabetes are living longer (due to improved disease management), and hemoglobin A1c diagnostic tests are now used and previous estimates are not directly comparable.

Approximately 5-10% have type 1 diabetes, 90-95% have type 2 diabetes, and 1-5% have other types. With increasing numbers of the obese, the elderly, and members of higherrisk minority groups in the population, prevalence is increasing.

International statistics
Type 2 diabetes mellitus is less common in non-Western countries where the diet contains fewer calories and daily caloric expenditure is higher. However, as people in these countries adopt Western lifestyles, weight gain and type 2 diabetes mellitus are becoming virtually epidemic. Rates of diabetes are increasing worldwide. At least 171 million people currently have diabetes, and this figure is likely to more than double to 366 million by 2030. The top 10 countries, in numbers of people with diabetes, are currently India, China, the United States, Indonesia, Japan, Pakistan, Russia, Brazil, Italy, and Bangladesh. The greatest percentage increase in rates of diabetes will occur in Africa over the next 20 years. However, at least 80% of people in Africa with diabetes are undiagnosed, and many in their 30s to 60s will die from diabetes there.

Type 2 diabetes in racial minorities

The prevalence of type 2 diabetes mellitus varies widely among various racial and ethnic groups. The image below shows data for various groups. Type 2 diabetes mellitus is more prevalent among Hispanics, Native Americans, African Americans, and Asians/Pacific Islanders than in nonHispanic whites. Indeed, the disease is becoming virtually pandemic in some groups of Native Americans and Hispanic people. The risk of retinopathy and nephropathy appears to be greater in blacks, Native Americans, and Hispanics.

Prevalence of diabetes mellitus type 2 in various racial and ethnic groups in the United States (2007 estimates).

In a study by Selvin et al, differences between blacks and whites were noted in many glycemic markers and not just the HbA1c level.[15] This suggests real differences in glycemia. rather than glycation process or the erythrocyte turnover, between blacks and whites. Type 2 diabetes mellitus occurs most commonly in adults aged 40 years or older, and the prevalence of the disease increases with advancing age. Indeed, the aging of the population is one reason that type 2 diabetes mellitus is becoming increasingly common. Virtually all cases of diabetes mellitus in older individuals are type 2. In addition, however, the incidence of type 2 diabetes is increasing more rapidly in adolescents and young adults than in other age groups. The disease is being recognized increasingly in younger persons, particularly in highly susceptible racial and ethnic groups and the obese. In some areas, more type 2 than type 1 diabetes mellitus is being diagnosed in prepubertal children, teenagers, and young adults. The prevalence of diabetes mellitus by age is shown in the image below.

Prevalence of diabetes mellitus type 2 by age in the United States (2007 estimates).

Diabetes-associated mortality and morbidity

Diabetes mellitus is one of the leading causes of morbidity and mortality in the United States because of its role in the development of cardiovascular, renal, neuropathic, and retinal disease. These complications, particularly cardiovascular disease (approximately 50-75% of medical expenditures), are the major sources of expenses for patients with diabetes mellitus. Approximately two thirds of people with diabetes die of heart disease or stroke. Men with diabetes face a 2-fold increased risk for coronary heart disease, and women have a 3- to 4fold increased risk. In 1994, 1 of every 7 health care dollars in the United States was spent on patients with diabetes mellitus. The 2002 estimate for direct medical costs due to diabetes in the United States was $92 billion, with another $40 billion in indirect costs. Approximately 20% of Medicare funds are spent on these patients. Diabetes mellitus is the major cause of blindness in adults aged 20-74 years in the United States; diabetic retinopathy accounts for 12,000-24,000 newly blind persons every year. [16] The National Eye Institute estimates that laser surgery and appropriate follow-up care can reduce the risk of blindness from diabetic retinopathy by 90%.[16] Diabetes mellitus, and particularly type 2 diabetes mellitus, is the leading contributor to end-stage renal disease (ESRD) in the United States.[16]According to the Centers for Disease Control and Prevention, diabetes accounts for 44% of new cases of ESRD.[14] In 2005, 46,739 people in the United States and Puerto Rico began renal replacement therapy, and 178,689 people with diabetes were on dialysis or had received a kidney transplant.[16]

Diabetes mellitus is the leading cause of nontraumatic lower limb amputations in the United States, with a 15- to 40-fold increase in risk over that of the nondiabetic population. In 2004, about 71,000 nontraumatic lower limb amputations were performed related to neuropathy and vasculopathy.[16] The risk for coronary heart disease is 2-4 times greater in patients with diabetes than in individuals without diabetes. Cardiovascular disease is the major source of mortality in patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus, a fasting glucose level of more than 100 mg/dL significantly contributes to the risk for cardiovascular disease and death, independent of other known risk factors. [17] This is based on a review of 97 prospective studies involving 820,900 patients. A 2010 Consensus Report from a panel of experts chosen jointly by the American Diabetes Association and the American Cancer Society suggested that people with type 2 diabetes are at an increased risk for many types of cancer.[18] Women with depression have a relative higher risk for diabetes. Women with diabetes have higher risk for depression, particularly in those receiving insulin, which might reflect a complicated and poor glycemic state.[19] A meta-analysis determined that individuals with type 2 diabetes have a 24% increased risk of developing depression, although the mechanisms behind this relationship require further studies.[20] The prognosis in patients with diabetes mellitus is strongly influenced by the degree of control of their disease. Chronic hyperglycemia is associated with an increased risk of microvascular complications, as shown in the Diabetes Control and Complications Trial (DCCT) in individuals with

type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in people with type 2 diabetes.[21] In the DCCT, intensive therapy to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, and neuropathy over 7 years. The Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that followed the patients previously enrolled in the DCCT, demonstrated that benefit has continued since the DCCT trial ended in 1993--a sort of legacy effect.[22, 23] In the UKPDS, more than 5000 patients with type 2 diabetes were followed up for up to 15 years. Those in the intensely treated group had a significantly lower rate of progression of microvascular complications than that of those receiving standard care. Rates of macrovascular disease were not altered except in the metformin-monotherapy arm in obese individuals, in which the risk of MI was significantly decreased. Moreover, severe hypoglycemia occurred less often than it did in patients with type 1 diabetes in the DCCT. In the 10-year follow-up to the UKPDS, there was a continued reduction in microvascular and all-cause mortality, as well as cardiovascular events in the previously intensively treated group (total follow-up of 20 years, half while in the study and half after the study ended). Other, shorter studies such as ACCORD, Advance, and VADT showed no improvement in cardiovascular disease (CVD) events and death with tight control (lower targets than in UKPDS).[24, 25, 26] Additionally, in the ACCORD study, there was an increase in overall mortality with more intensive control. The patients in these 3 studies had a longer duration

of disease and had a prior CVD event or were at high risk for a CVD event. This is in contrast to the UKPDS study in which patients were younger, with new-onset disease and low rates of CVD. Overall, these studies suggest the following: tight glycemic control (HbA1C < 7% or lower) is valuable in terms of microvascular and macrovascular disease risk reduction in patients with recent-onset disease, no known CVD, and a longer life expectancy. In patients with known CVD, a longer duration of diabetes (15 or more years), and a shorter life expectancy, tighter glycemic control is not as beneficial, particularly regarding CVD risk. Efforts should be undertaken to avoid episodes of severe hypoglycemia, as these events may be particularly harmful in older individuals with poorer glycemic control and existing CVD. One prospective study with a long follow-up challenges the concept of coronary disease risk equivalency between nondiabetic patients with a first myocardial infarction and patients with type 2 diabetes but without any cardiovascular disease. The study found that patients with type 2 diabetes had lower long-term cardiovascular risk compared with patients with first myocardial infarction. Other studies have similarly questioned this risk equivalency.[27] Patients with diabetes have a lifelong challenge to achieve and maintain blood glucose levels as close to the reference range as possible. With appropriate glycemic control, the risk of microvascular and neuropathic complications is decreased markedly. In addition, if hypertension and hyperlipidemia are treated aggressively, the risk of macrovascular complications decreases as well.

These benefits are weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. Studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years after starting effective preventive care. Some studies suggest that broad-based focus on treatment (eg, glycemia, nutrition, exercise, lipids, hypertension, smoking cessation) is much more likely to reduce the burden of excess microvascular and macrovascular events.