Diabetes Mellitus

Diabetes mellitus is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose that is caused by a relative or absolute deficiency of insulin (Fig. 1). Diabetes is the leading cause of adult blindness and amputation and a major cause of renal failure, nerve damage, heart attacks, and stroke. Diabetes can be classified into two groups, type 1 (T1D) and type 2 (T2D). T1D constitutes ~10% of >29 million cases of diabetes in the United States. The disease is characterized by an absolute deficiency of insulin caused by an autoimmune attack on the pancreatic β cells. This destruction requires an environmental stimulus (such as a viral infection) and a genetic determinant that causes the β cell to be mistakenly identified as “nonself.” The metabolic abnormalities of T1D include hyperglycemia, diabetic ketoacidosis (DKA), and hypertriacylglycerolemia that result from a deficiency of insulin. Those with T1D must rely on exogenous insulin delivered subcutaneously to control hyperglycemia and ketoacidosis. T2D has a strong genetic component. It results from a
combination of insulin resistance and dysfunctional β cells.

Insulin resistance is the decreased ability of target tissues, such as liver, white adipose, and skeletal muscle, to respond properly to normal (or elevated) circulating concentrations of insulin. Obesity is the most common cause of insulin resistance. However, most people with obesity and insulin resistance do not develop diabetes. In the absence of a defect in β-cell function, obese individuals without diabetes can compensate for insulin resistance with elevated levels of insulin. Insulin resistance alone will not lead to T2D. Rather, T2D develops in insulin-resistant individuals who also show impaired β-cell function. The acute metabolic alterations observed in T2D are milder than those described for the insulin-dependent form of the disease, in part because insulin secretion in T2D, although inadequate, does restrain ketogenesis and blunts the development of DKA. Available treatments for diabetes moderate the hyperglycemia but fail to completely normalize metabolism. The long-standing elevation of blood glucose is associated with the chronic complications of diabetes including cardiovascular disease and stroke (macrovascular) as well as retinopathy, nephropathy, and neuropathy (microvascular).

Figure 1:  Key concept map for diabetes. [Note: Data are from 2014.] GLUT = glucose transporter.