Insulin Resistance

Insulin resistance is the decreased ability of target tissues, such as the liver, white adipose, and skeletal muscle, to respond properly to normal (or elevated) circulating concentrations of insulin. For example, insulin resistance is characterized by increased hepatic glucose production, decreased glucose uptake by muscle and adipose tissue, and increased adipose lipolysis with production of free fatty acids (FFA).
1. Insulin resistance and obesity: Although obesity is the most common cause of insulin resistance and increases the risk of T2D, most people with obesity and insulin resistance do not develop diabetes. In the absence of a defect in β-cell function, obese individuals can compensate for insulin resistance with elevated levels of insulin. For example, Figure 1 A shows that insulin secretion is two to three times higher in obese subjects than it is in lean individuals. This higher insulin concentration compensates for the diminished effect of the hormone (as a result of insulin resistance) and produces blood glucose levels similar to those observed in lean individuals (Fig. 1B).

Figure 1: Blood insulin (A) and blood glucose levels (B) in normal-weight and obese subjects.
2. 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 2 shows the time course for the development of hyperglycemia and the loss of β-cell function.

Figure 2: Progression of blood glucose and insulin levels in patients with type 2 diabetes.
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. 3). 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 , 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. 3).
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 . Consequently, a decrease in this adipocyte protein contributes to FFA availability.]

Figure 3: Obesity, insulin resistance, and hyperglycemia. [Note: Inflammation also is associated with insulin resistance.]