Improving Insulin Sensitivity: A Review of New Therapies

Insulin resistance is a state of impaired insulin action in insulin—dependent tissues-liver, muscle, and fat tissues. Impaired insulin action results in a reduction in insulin-stimulated glucose uptake and impaired insulin-mediated suppression of hepatic glucose production and adipocyte lipolysis. Insulin resistance may result from a disruption in any step of the insulin-signaling cascade. Defects in insulin signaling have been demonstrated in association with clinical predictors of insulin resistance, such as obesity, lack of physical activity, and a family history of type 2 diabetes mellitus. Weight loss and physical activity have been shown to improve insulin sensitivity in patients with diabetes. For many years, metformin and thiazolidinediones were the only pharmacologic treatments available that targeted insulin resistance; however, new classes of drugs, including the incretin analogs, dipeptidylpeptidase (DPP)-4 inhibitors, and endocannabinoid inhibitors, have been discovered. Incretins are intestinal hormones that are released in response to nutrient ingestion to stimulate insulin secretion by the β-cells of the pancreatic islets. Incretin analogs improve insulin secretion and insulin sensitivity and promote weight loss. DPP-4 inhibitors block DPP-4, an enzyme that degrades the endogenous incretin hormone glucagon-like peptide-1. DPP-4 inhibitors stimulate insulin secretion, inhibit glucagon secretion, and increase postmeal insulin sensitivity, but they do not appear to promote weight loss. Pharmacologic blockade of CB1 receptors with endocannabinoid inhibitors has been shown to reduce food intake, promote weight loss, and increase adiponectin levels. These treatments may not only improve glycemic control but also offer the potential for additional metabolic and cardiovascular benefits.