The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes

The pathophysiology of type 2 diabetes mellitus (DM) is varied and complex.However, the association of DM with obesity and inactivity indicates an important, and potentially pathogenic, link between fuel and energy homeostasis and the emergence of metabolic disease.Given the central role for mitochondria in fuel utilization and energy production, disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis.Thus, the hypothesis that defective or insufficient mitochondrial function might play a potentially pathogenic role in mediating risk of type 2 DM has emerged in recent years.Here, we summarize current literature on risk factors for diabetes pathogenesis, on the specific role(s) of mitochondria in tissues involved in its pathophysiology, and on evidence pointing to alterations in mitochondrial function in these tissues that could contribute to the development of DM.We also review literature on metabolic phenotypes of existing animal models of impaired mitochondrial function.We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain.However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load.This imbalance may lead in turn to chronic accumulation of lipid oxidative metabolites that can mediate insulin resistance and secretory dysfunction.More refined experimental strategies that accurately mimic potential reductions in mitochondrial functional capacity in humans at risk for diabetes will be required to determine the potential pathogenic role in human insulin resistance and type 2 DM.(Endocrine Reviews 31: 364 -395, 2010) I. Type 2 Diabetes Pathogenesis A. Risk factors associated with type 2 diabetes II.General Overview of Mitochondrial Biology A. The dynamic morphology of mitochondria B. Mechanisms that control mitochondrial density and capacity III.Role of Mitochondria in Tissue-Specific Contexts A. Muscle B. Adipose tissue C. Liver D. Pancreatic ␤-cells IV.Experimental Strategies to Explore the Relationship between Mitochondrial Function and DM A. PGC-1 ␣ and ␤ overexpression B. PGC-1 knockout models C. Other mitochondrial function defects V. Conclusions I. Type 2 Diabetes Pathogenesis T ype 2 diabetes mellitus (DM) in the United States and around the world has reached epidemic proportions.At present, 17.9 million people in the United States have been diagnosed with diabetes, with an additional 5.7 million undiagnosed (1).Together, this encompasses 8% of the population, and thus, diabetes is a major public health issue.In addition, current data indicate that 57 million Americans suffer from prediabetes (defined as fasting blood glucose between 100 and 125 mg/dl) (1).Diabetes disproportionately affects specific ethnic populations, with risk increased 1.8-fold in African-Americans, 1.7fold in Mexican-Americans, and 2.2-fold in Native Amer-