Assessment of insulin resistance in vivo: application to the study of type 2 diabetes

Abstract

Besides insulin secretion, insulin sensitivity plays a key role in the feedback glucose-insulin closed loop. It can be altered in numerous physiological, pathological and pharmacological conditions. It can be estimated in vivo using methods that open the feedback loop (insulin suppression test, glucose clamp) or that analyze the closed loop by employing mathematical models of glucose kinetics. The most popular method is the euglycemic hyperinsulinemic glucose clamp. This test should be ideally coupled with a priming-constant infusion of a glucose tracer together with indirect calorimetry. This combination allows to study the glucose kinetics (Ra and Rd, and thus endogenous-mainly hepatic-glucose production) and its metabolism (oxidation or storage as glycogen), respectively. One alternative approach is the frequently sampled intravenous glucose tolerance test where the dynamic changes in plasma insulin and glucose levels are analyzed using the so-called 'minimal model' method. Noninsulin-dependent or type 2 diabetes is characterized by a significant defect in both insulin secretion and action. The insulin resistance is located at the liver site (increased glucose production) and at the peripheral tissues (decreased oxidation and, even more, defective storage of glucose in the muscles). This insulin resistance, which predominates at the postreceptor level, seems to be genetically determined but is worsened by weight excess and by hyperglycemia itself. This contributes to a vicious circle which aggravates progressively the severity of the disease.