Fig.20.23Developmentoftype2diabetes.Insulinresistanceassociatedwithobesityisinducedbyadipokines,freefattyacids,andchronicinflammationinadiposetissue.Pancreaticβ cellscompensateforinsulinresistancebyhypersecretionofinsulin.However,atsomepoint,β cellcompensationisfollowedbyβ cellfailure,anddiabetesensues.(Reproduced with permission from Kasuga M: Insulin resistance and pancreatic β-cell failure. JClinInvest116:1756, 2006.) early in the disease process, the islets show necrosis of beta cells and lymphocytic infiltration (so-called “insulitis”, described later).
Type 2 diabetes is a heterogeneous and multifactorial complex disease that involves interactions of genetics, environmental risk factors, and inflammation. Unlike type 1 diabetes, however, there is no evidence of an autoimmune basis. The two defects that characterize type 2 diabetes are: (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and (2) beta cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia (
Fig. 20.23 ). Insulin resistance predates the development of hyperglycemia and usually is accompanied by compensatory beta cell hyperfunction and hyperinsulinemia in the early stages of the evolution of diabetes.
Environmental factors, such as a sedentary lifestyle and dietary habits, unequivocally play a role, as described in the subsequent discussion of the association with obesity. Genetic factors also are involved, as evidenced by a concordance rate of 80% to 90% in monozygotic twins, which is even greater than that for type 1 diabetes (approximately 50% concordance rates in twins), suggesting perhaps an even larger genetic component in type 2 diabetes. Additional evidence for a genetic basis has emerged from recent large-scale genome-wide association studies, which have identified dozens of susceptibility loci called diabetogenic genes. Unlike type 1 diabetes, however, the disease is not linked to genes involved in immune tolerance and regulation (e.g., HLA, CTLA4).
Insulin resistance is defined as the failure of target tissues to respond normally to insulin. The liver, skeletal muscle, and adipose tissue are the major tissues where insulin resistance manifests as follows:
Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver, which contributes to high fasting blood glucose levels
Abnormally low glucose uptake and glycogen synthesis in skeletal muscle following a meal, which contributes to a high postprandial blood glucose level
Failure to inhibit hormone-sensitive lipase in adipose tissue, leading to excess circulating free fatty acids (FFAs), which, as will be discussed, exacerbates the state of insulin resistance
Few factors play as important a role in the development of insulin resistance as obesity. The association of obesity with type 2 diabetes has been recognized for decades, with visceral obesity being common in a majority of affected patients. Insulin resistance is present even with simple obesity unaccompanied by hyperglycemia, indicating a fundamental abnormality of insulin signaling in states of fat excess. The term metabolic syndrome has been applied to a constellation of findings dominated by visceral obesity, accompanied by insulin resistance, glucose intolerance, and cardiovascular risk factors such as hypertension and abnormal lipid profiles. Individuals with metabolic syndrome are at high risk for the development of type 2 diabetes.