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Diabetes Mellitus, Type 2

Introduction
Background

Type 2 diabetes mellitus is a group of disorders characterized by hyperglycemia and associated with microvascular (ie, retinal, renal, possibly neuropathic), macrovascular (ie, coronary, peripheral vascular), and neuropathic (ie, autonomic, peripheral) complications. Unlike type 1 diabetes mellitus, patients are not absolutely dependent upon insulin for life, even though many of these patients are ultimately treated with insulin.

Pathophysiology

Hyperglycemia is produced by lack of endogenous insulin, which is either absolute, as in type 1 diabetes mellitus, or relative, as in type 2 diabetes mellitus. Relative insulin deficiency usually occurs because of resistance to the actions of insulin in muscle, fat, and the liver and an inadequate response by the pancreatic beta cell. This pathophysiologic abnormality results in decreased glucose transport in muscle, elevated hepatic glucose production, and increased breakdown of fat.

The genetics of type 2 diabetes are complex and not completely understood, but presumably this disease is related to multiple genes (with the exception of maturity-onset diabetes of the young [MODY]). Evidence supports inherited components for both pancreatic beta cell failure and insulin resistance. Considerable debate exists regarding the primary defect in type 2 diabetes mellitus. Most patients have both insulin resistance and some degree of insulin deficiency. However, insulin resistance per se is not the sine qua non for type 2 diabetes mellitus because many people with insulin resistance (particularly patients who are obese) do not develop glucose intolerance. Therefore, insulin deficiency is necessary for the development of hyperglycemia. Patients may have high insulin levels, but the insulin concentrations are inappropriately low for the level of glycemia.
MODY is associated with autosomal dominant inheritance and is characterized by onset in at least 1 family member younger than 25 years, correction of fasting hyperglycemia without insulin for at least 2 years, and absence of ketosis. At least 6 genetically different types of MODY have been described. Some patients ultimately require insulin to control glycemia.

Recent work has suggested that elevated free fatty acids may be the driving force behind insulin resistance and perhaps even beta cell dysfunction. If this defect is more proximal than defects specifically related to glycemia, then therapies aimed at correcting this phenomenon would be highly beneficial.

Presumably, the defects of type 2 diabetes mellitus occur when a diabetogenic lifestyle (ie, excessive calories, inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype. The extent of excess weight may vary with different groups. For example, overweight patients from Asia may not be overweight by Western standards, but excess weight is often much more pronounced in these ethnic groups. Recent work suggests that in utero environment resulting in low birth weight may predispose some individuals to develop type 2 diabetes mellitus. The pathophysiology of abnormal glucose metabolism in type 2 diabetes mellitus is simply depicted in Image 1.

Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However, glycemia is much less related to macrovascular disease. Insulin resistance with concomitant lipid (ie, small dense low-density lipoprotein [LDL] particles, low high-density lipoprotein-cholesterol [HDL-C] levels, elevated triglyceride-rich remnant lipoproteins) and thrombotic (ie, elevated type-1 plasminogen activator inhibitor [PAI-1], elevated fibrinogen) abnormalities, as well as conventional atherosclerotic risk factors (eg, family history, smoking, hypertension, elevated low-density lipoprotein-cholesterol [LDL-C], low HDL-C), determine cardiovascular risk.

Increased cardiovascular risk appears to begin prior to the development of frank hyperglycemia, presumably because of the effects of insulin resistance. Stern in 1996 and Haffner and D’Agostino in 1999 developed the “ticking clock” hypothesis of complications, asserting that the clock starts ticking for microvascular risk at the onset of hyperglycemia, while the clock starts ticking for macrovascular risk at some antecedent point, presumably with the onset of insulin resistance.1

Frequency
United States

In 2002, the estimated prevalence of diabetes in the United States was 6.3% (18.2 million people); approximately one quarter of cases were undiagnosed. More than 90% of cases of diabetes are type 2 diabetes mellitus. With increasing obesity in the population, an older population, and an increase in the population of higher-risk minority groups (see Race), prevalence is increasing.
International

Type 2 diabetes mellitus is less common in non-Western countries where the diet contains fewer calories and caloric expenditure on a daily basis is higher. However, as people in these countries adopt Western lifestyles, weight gain and type 2 diabetes mellitus are becoming virtually epidemic.
Mortality/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 optic, renal, neuropathic, and cardiovascular disease. These complications, particularly cardiovascular disease (~50-75% of medical expenditures), are the major sources of expenses for patients with diabetes mellitus. Approximately two thirds of people with diabetes die from heart disease or stroke. Men with diabetes face a 2-fold increased risk for coronary heart disease, and women have a 3- to 4-fold 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 is the leading cause of blindness in working-age adults in the United States, accounting for 12,000-24,000 newly blind persons every year. The National Eye Institute estimates that 90% of cases of lost vision are preventable.
Diabetes mellitus is the leading cause of end-stage renal disease (ESRD) accounting for 44% of new cases according to the Centers for Disease Control and Prevention (CDC). In 2001, 42,813 people began renal replacement therapy, and 142,963 people with diabetes were on dialysis or had received a kidney transplant.
Diabetes mellitus is the leading cause of nontraumatic lower limb amputations in the United States, with a 15- to 40-fold increase in risk compared to that of the nondiabetic population. In 2000-2001, about 82,000 nontraumatic lower limb amputations were performed related to neuropathy and vasculopathy.
Race
The prevalence of type 2 diabetes mellitus varies widely among various racial and ethnic groups. Image 2 shows data for various groups. Type 2 diabetes mellitus is becoming virtually pandemic in some groups of Native Americans and Hispanic people. Recent work suggests more retinopathy and nephropathy in blacks, Native Americans, and Hispanic groups.
Sex

Type 2 diabetes mellitus is slightly more common in older women than men.
Age

While type 2 diabetes mellitus traditionally has been thought to affect individuals older than 40 years, it is being recognized increasingly in younger persons, particularly in highly susceptible racial and ethnic groups. In some areas, more type 2 than type 1 diabetes mellitus is being diagnosed in prepubertal children, teenagers, and young adults. Type 2 diabetes mellitus is observed even in some obese children. The effects of age on the prevalence of diabetes mellitus are shown in Image 3. Virtually all cases of the disease in older individuals are type 2 diabetes mellitus.
Clinical
History
While a diagnosis of diabetes mellitus is readily entertained when a patient presents with classic symptoms (ie, polyuria, polydipsia, polyphagia, weight loss), most patients with type 2 diabetes mellitus are asymptomatic for years. Other symptoms that might suggest hyperglycemia include blurred vision, lower extremity paresthesias, or yeast infections, particularly balanitis in men. However, the asymptomatic state does not mean that hyperglycemia is not affecting the individual.
The possible presence of diabetes mellitus should be considered in obese patients, patients with a first-degree relative with type 2 diabetes mellitus, members of high-risk ethnic groups (ie, black, Hispanic, Native American, Asian American, Pacific Islander), women with a previous delivery of a large infant (>9 lb) or with a history of gestational diabetes mellitus, patients with hypertension, or patients with high triglycerides (>250 mg/dL) or low HDL-C (<35 mg/dL). While the United States Public Health Service and the American College of Physicians do not recommend routine screening for diabetes, targeted screening may be useful.
Because polycystic ovary disease is an insulin-resistant state, screening these women may be warranted.
Whether at-risk persons should be screened for prediabetes is unclear at present. The therapy would generally be lifestyle changes to facilitate weight loss and improve cardiovascular fitness, and in virtually all cases, this would be the recommendation for such patients without a measured glucose value.
Physical

Early in the course of diabetes mellitus, the physical examination findings are likely to be unrevealing. However, ultimately, end-organ damage may be observed. Potential findings are listed in Image 4.
Causes
Superimposition of caloric excess (usually in the form of a high-fat diet accompanied by minimal excess caloric expenditure) upon a susceptible genotype appears to cause type 2 diabetes mellitus.
Diabetes mellitus may be caused by other conditions. Secondary diabetes may occur in patients taking glucocorticoids or when patients have conditions that antagonize the actions of insulin (eg, Cushing syndrome, acromegaly, pheochromocytoma).

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