It is not only the absolute amount but also the distribution of body fat that has an effect on insulin sensitivity: central obesity (abdominal fat) is more likely to be associated with insulin resistance than is peripheral (gluteal/ subcutaneous) obesity. Obesity can adversely impact insulin sensitivity in numerous ways (see
Fig. 20.23
Excess FFAs. Cross-sectional studies have demonstrated an inverse correlation between fasting plasma FFAs and insulin sensitivity. The level of intracellular triglycerides often is markedly increased in muscle and liver in obese individuals, presumably because excess circulating FFAs are taken up into these organs. Central adipose tissue is more “lipolytic” than peripheral adipose tissue, which might explain the particularly deleterious consequences of the central pattern of fat distribution. Intracellular triglycerides and products of fatty acid metabolism are potent inhibitors of insulin signaling and result in an acquired insulin resistance state.
Adipokines. Adipose tissue is not merely a passive storage depot for fat; it also is an endocrine organ that releases hormones in response to changes in metabolic status. A variety of proteins secreted into the systemic circulation by adipose tissue have been identified that are known collectively as adipokines (or adipose cytokines). Some of these promote hyperglycemia, and others (such as leptin and adiponectin) decrease blood glucose, in http://ebooksmedicine.net part by increasing the insulin sensitivity of peripheral tissues. Adiponectin levels are decreased in obesity, thus contributing to insulin resistance.
• Inflammation. Over the past several years, inflammation has emerged as an important contributor to the pathogenesis of type 2 diabetes. It is now known that a permissive inflammatory milieu (mediated by proinflammatory cytokines that are secreted in response to excess nutrients such as FFAs) results in both peripheral insulin resistance and beta cell dysfunction (discussed later). Excess FFAs within macrophages and beta cells can activate the inflammasome, a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin (IL-1β; Chapter 5). IL-1β stimulates the secretion of additional proinflammatory cytokines from macrophages, islets, and other cells, and IL-1 as well as other cytokines promote insulin resistance in peripheral tissues. Thus, excess FFAs can impede insulin signaling directly, as well as indirectly through the release of cytokines.
While insulin resistance by itself can lead to impaired glucose tolerance, beta cell dysfunction is an essential component in the development of overt diabetes. Beta cell function actually increases early in the disease process in most patients with type 2 diabetes, mainly as a compensatory measure to counter insulin resistance and maintain euglycemia. Eventually, however, beta cells are unable to adapt to the long-term demands of peripheral insulin resistance, and the hyperinsulinemic state gives way to a state of relative insulin deficiency.
Several mechanisms have been implicated in causing beta cell dysfunction in type 2 diabetes, including the following:
Abnormal incretin effect, leading to reduced secretion of hormones that promote insulin release (discussed earlier)
Amyloid replacement of islets, present in more than 90% of diabetic islets (see ). It is unclear whether the amyloid is a cause or effect of beta cell “burnout.”
Polymorphisms associated with an increased lifetime risk for type 2 diabetes in genes that control insulin secretion.
Type 1 and type 2 diabetes are genetically complex, and despite the associations with multiple susceptibility loci, no single-gene defect (mutation) can account for predisposition to these diseases. By contrast, monogenic forms of diabetes (see