Insulin resistance alone does not lead to type 2 diabetes (T2D). Instead, T2D develops in individuals who are both insulin-resistant and have impaired β-cell function. The risk of developing T2D is commonly observed in obese individuals, those who are physically inactive or elderly, and in around 3%–5% of pregnant women who have gestational diabetes. These patients are unable to adequately compensate for insulin resistance through increased insulin release. Figure 25.8 illustrates the timeline for the development of hyperglycemia and the loss of β-cell function.

Insulin resistance is influenced by weight gain, with increased weight leading to increased resistance and weight loss resulting in decreased resistance. Excess adipose tissue, particularly in the abdomen, plays a significant role in the development of insulin resistance. Adipose tissue is not only an energy storage tissue but also a secretory tissue. In cases of obesity, there are changes in adipose secretions that contribute to insulin resistance (Fig. 25.9). These changes include the secretion of proinflammatory cytokines like interleukin 6 and tumor necrosis factor-α by activated macrophages, increased synthesis of the proinflammatory protein leptin, and decreased secretion of the anti-inflammatory protein adiponectin. These factors collectively contribute to chronic, low-grade inflammation. Insulin resistance also leads to increased lipolysis and production of free fatty acids (FFA), resulting in decreased glucose utilization, elevated blood glucose levels (hyperglycemia), and deposition of triglycerides (TAG) in the liver, known as hepatic steatosis. Hepatic steatosis can progress to nonalcoholic fatty liver disease (NAFLD), and if accompanied by inflammation, it can develop into a more serious condition called nonalcoholic steatohepatitis (NASH). FFA also have proinflammatory effects and in the long term impair insulin signaling. Adiponectin, on the other hand, promotes fatty acid β-oxidation, so a decrease in its levels contributes to increased availability of FFA.

In type 2 diabetes, the pancreatic β-cells initially maintain their capacity to produce insulin, resulting in varying insulin levels ranging from above normal to below normal. However, over time, these β-cells become increasingly dysfunctional and fail to secrete sufficient insulin to regulate the prevailing hyperglycemia. For instance, insulin levels in typical obese individuals with T2D are high but not as high as in similarly obese individuals without diabetes. This natural progression of the disease leads to a diminishing ability to control hyperglycemia through the body's own insulin secretion (Fig. 25.10). The deterioration of β-cell function can be accelerated by the toxic effects of sustained hyperglycemia, elevated FFA levels, and a proinflammatory environment.

The abnormalities in glucose and TAG metabolism seen in T2D primarily stem from insulin resistance in the liver, skeletal muscle, and white adipose tissue (Fig. 25.11).

Hyperglycemia in T2D is caused by increased production of glucose by the liver coupled with reduced utilization of glucose by muscle and adipose tissues. Ketone buildup in the blood (ketonemia) is usually minimal or absent in T2D patients because insulin, despite resistance, still inhibits ketogenesis in the liver.
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.