The Epidemic of Type 2 Diabetes Mellitus: Its Links to Obesity, Insulin Resistance, and Lipotoxicity

Abstract

The epidemic of type 2 diabetes (T2DM) is a public health problem thatthreatens to spiral out of control in the twenty-first century. Earlyintervention can greatly mitigate the serious socioeconomic impact ofthe disease, driven largely by disabling microvascular complications andcardiovascular disease. Obesity is at the core of the epidemic of T2DM,affecting 2/3 of adults and reaching alarming rates in children inmodern society. Our understanding of adipose tissue has evolveddrastically in the past decade being now viewed as a dynamic ``endocrineorgan{''} responsible for the development or worsening of insulinresistance and ``lipotoxicity{''} in obese individuals.``Lipotoxicity{''} describes the damage that occurs when chronic energysupply exceeds metabolic needs and lipid accumulates in tissues thatwould not normally store large amounts of lipid. In this setting, lipidis redirected into harmful pathways of nonoxidative metabolism, withaccumulation of toxic metabolites that activate inflammatory pathwaysand eventually lead to apoptosis. It affects organs responsible formaintaining normal energy homeostasis, such as the liver, skeletalmuscle, and pancreatic beta-cells, but also the vascular bed. Theability of fatty acids to disrupt insulin signaling and how themitochondria adapts to chronic lipid overload are essential steps inunderstanding FFA-induced insulin resistance and lipotoxicity acrossdifferent tissues. Interventions that may prevent lipotoxicity indifferent target tissues, but in particular pancreatic beta-celllipotoxicity, such as exercise, weight loss, and/or pharmacologicaltherapies such as thiazolidinediones, hold the key to prevent diabetesin subjects genetically predisposed to T2DM. and tackle the loomingepidemic of the coming century.