Defects in Insulin Secretion and Action in the Pathogenesis of Type 2 Diabetes Mellitus Devjit Tripathy & Alberto O. Chavez Published online: 15 April 2010 # Springer Science+Business Media, LLC 2010 Abstract Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin action and insulin secretion. Although insulin resistance manifests early during the prediabetic state, a failing β-cell function unable to overcome insulin resistance at target tissues determines the onset of T2DM. This review focuses on recent advances in the molecular mechanisms of insulin resistance and β-cell dysfunction. The role of mitochondrial dysfunction, impaired regulation of the enter- oinsular axis, and endoplasmic reticulum stress are currently the subjects of intensive research. In addition, the adipose tissue has emerged as a major endocrine organ that secretes a growing list of adipocytokines with diverse central and peripheral metabolic effects. The role of a growing number of candidate genes and transcription factors regulating insulin action and secretion is also discussed. Keywords Type 2 diabetes mellitus . Insulin resistance . Insulin secretory defects . Mitochondrial dysfunction . Free fatty acids . Adipokines . Incretins Introduction The pathogenesis of type 2 diabetes mellitus (T2DM) has been studied extensively and it is well established that although genetic factors predispose, it is the environmental factors (ie, overnutrition and a sedentary lifestyle) that pull the trigger to manifest the disease. Type 2 diabetes is character- ized by two fundamental defects: impaired insulin action in skeletal muscle, liver, and adipocytes, and impaired β-cell function [1••]. The relative contribution of insulin resistance versus pancreatic β-cell dysfunction to the pathogenesis of T2DM is still a cause of debate. The present review focuses on the recent advances in the understanding of T2DM pathogenesis, including the underlying molecular and meta- bolic basis of insulin resistance, and the mechanisms responsible for impaired β-cell function. Normal Glucose Metabolism In healthy individuals, plasma glucose levels are maintained within a very narrow range. Any given concentration of glucose in plasma is the result of simultaneous release of glucose into circulation and uptake of glucose from plasma by the cells. The liver is the primary source of endogenous glucose production (EGP), although kidneys contribute ap- proximately 5% to 10% of EGP in the basal state. Following glucose or meal ingestion, a rise in plasma glucose leads to insulin release from β cells and the hyperinsulinemia stimulates glucose uptake by splanchnic (liver and gut) and peripheral tissue (primarily muscle). From a physiologic perspective, it is clear that any defects in insulin secretion in response to a meal or defects in insulin action in peripheral tissue will lead to increased plasma glucose. Although impaired insulin action has been reported in other tissues such as the brain and myocardium, we limit our discussion to insulin action in the skeletal muscle, liver, and the adipose tissue. Defects in Insulin Action The notion that people with T2DM have impaired insulin action due to insulin resistance has been known for several D. Tripathy (*) : A. O. Chavez Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA e-mail: tripathy@uthscsa.edu Curr Diab Rep (2010) 10:184–191 DOI 10.1007/s11892-010-0115-5