Insulin resistance and type 2 diabetes: Insulin resistance alone will not lead to T2D. Rather, T2D develops in insulin-resistant individuals who also show impaired β-cell function. Insulin resistance and subsequent risk for the development of T2D is commonly observed in individuals who are obese, physically inactive, or elderly and in the 3%–5% of pregnant women who develop gestational diabetes. These patients are unable to sufficiently compensate for insulin resistance with increased insulin release. Figure 25.8 shows the time course for the development of hyperglycemia and the loss of β-cell function.
3.
Causes of insulin resistance: Insulin resistance increases with weight gain and decreases with weight loss, and excess adipose tissue (particularly in the abdomen) is key in the development of insulin resistance. Adipose is not simply an energy storage tissue, but also a secretory tissue. With obesity, there are changes in adipose secretions that result in insulin resistance (Fig. 25.9). These include secretion of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor-α by activated macrophages (inflammation is associated with insulin resistance); increased synthesis of leptin, a protein with proinflammatory effects (see p. 353 for additional effects of leptin); and decreased secretion of adiponectin (see p. 350), a protein with anti-inflammatory effects. The net result is chronic, low-grade inflammation. One effect of insulin resistance is increased lipolysis and production of FFA (see Fig. 25.9). FFA availability decreases use of glucose, contributing to hyperglycemia, and increases ectopic deposition of TAG in liver (hepatic steatosis). [Note: Steatosis results in nonalcoholic fatty liver disease (NAFLD). If accompanied by inflammation, a more serious condition, nonalcoholic steatohepatitis (NASH), can develop.] FFA also have a proinflammatory effect. In the long term, FFA impair insulin signaling. [Note: Adiponectin increases FA β-oxidation (see p. 349). Consequently, a decrease in this adipocyte protein contributes to FFA availability.]
B. Dysfunctional β cells
In T2D, the pancreas initially retains β-cell capacity, resulting in insulin levels that vary from above normal to below normal. However, with time, the β cell becomes increasingly dysfunctional and fails to secrete enough insulin to correct the prevailing hyperglycemia. For example, insulin levels are high in typical, obese, T2D patients but not as high as in similarly obese individuals who do not have diabetes. Thus, the natural progression of the disease results in a declining ability to control hyperglycemia with endogenous secretion of insulin (Fig. 25.10). Deterioration of β-cell function may be accelerated by the toxic effects of sustained hyperglycemia and elevated FFA and a proinflammatory environment.
C. Metabolic changes
The abnormalities of glucose and TAG metabolism in T2D are the result of insulin resistance expressed primarily in liver, skeletal muscle, and white adipose tissue (Fig. 25.11).
1.
Hyperglycemia: Hyperglycemia is caused by increased hepatic production of glucose, combined with diminished use of glucose by muscle and adipose tissues. Ketonemia is usually minimal or absent in patients with T2D because the presence of insulin, even in the presence of insulin resistance, restrains hepatic ketogenesis.
2.