The metabolic syndrome comprises multiple features, including visceral obesity, hypertension, dyslipidemia, and impaired glucose tolerance. This constellation of conditions has also become synonymous with insulin resistance syndrome, which may be a more appropriate term, as insulin resistance is likely a primary link between the components of the metabolic syndrome [1]. Insulin is an anabolic hormone that has the primary action of facilitating glucose uptake in skeletal and myocardial myocytes, hepatocytes, and adipocytes. In addition, insulin also regulates lipolysis and hepatic glucose production. Insulin resistance can be defined as a condition of decreased responsiveness of these target tissues to normal levels of circulating insulin, that is, a state of decreased insulin sensitivity [2]. Insulin resistance arises from both genetically determined and acquired metabolic defects [3][4][5]. This article outlines how abnormal insulin signaling and secretion, impaired glucose disposal, lipotoxicity, and pro-inflammatory cytokines exacerbate insulin resistance and result in the perturbations of the metabolic syndrome (Fig. 1).
Defective insulin secretion and signaling
Normally, elevated glucose levels stimulate pancreatic b cells to secrete insulin and decrease glucagon production. This leads to suppression of hepatic glucose production and increased glucose uptake in muscle, liver, and adipose tissues. In the state of insulin resistance, b cell dysfunction occurs, manifesting as a loss of first phase insulin secretion or the lack of immediate Dr. Derek LeRoith is presently a consultant and speaker, and receives an honorarium from Merck, Sanofi-Aventis, Pfizer, Takeda, and Novo Nordisk.