Aging and Insulin Resistance: Just Say iNOS

Abstract

The ubiquitous presence of insulin resistance cannot be understated. First brought to light by Himsworth and Kerr (1) in 1939, insulin resistance, defined as a subnormal response to a given dose of insulin, was ushered into prime time by Gerald Reaven (2), where it has remained at center stage. Insulin resistance is a major feature of type 2 diabetes (2). Insulin resistance is also associated with obesity, essential hypertension, dyslipidemia, nonalcoholic fatty liver disease, obstructive sleep apnea, and cancer (3). This cluster of maladies has been termed by Reaven as the “insulin resistance syndrome.” Therefore, an individual with insulin resistance is strongly predisposed to an increased risk of life-threatening clinical conditions, including cardiovascular disease. As Reaven points out, the clinical consequences of insulin resistance are not due to insulin resistance per se but come from the hyperinsulinemia that occurs as the individual with insulin resistance attempts to maintain normoglycemia. In reality, compensatory hyperinsulinemia is akin to cutting a deal with the devil. Chronic hyperinsulinemia may be beneficial to resistant tissues requiring it, for example to maintain insulin action in liver, muscle, and adipose tissues; however, it may wreak havoc with tissues that have normal sensitivity to insulin. Even within the same tissue, some of the insulin-regulated pathways, such as the glucose metabolic pathway, are more resistant to insulin than others, including the mitogenic pathway (4). Thus, it is likely that chronic overstimulation of the mitogenic pathway by insulin also plays a causative role in mediating the clinical consequences of insulin resistance. Therefore, intensive efforts are being directed toward identifying novel nutritional and pharmacological approaches that improve insulin sensitivity in target tissues. Our knowledge of …