REVIEW The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes Mary-Elizabeth Patti and Silvia Corvera Research Division, Joslin Diabetes Center (M.-E.P.), and Harvard Medical School (M.-E.P.), Boston, Massachusetts 02215; and Program in Molecular Medicine (S.C.), University of Massachusetts Medical School, Worcester, Massachusetts 01605 Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 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 meta- bolic 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. How- ever, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial ox- idative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxida- tive 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 I. Type 2 Diabetes Pathogenesis A. Risk factors associated with type 2 diabetes II. General Overview of Mitochondrial Biology ype 2 diabetes mellitus (DM) in the United States and A. The dynamic morphology of mitochondria B. Mechanisms that control mitochondrial density and T around the world has reached epidemic proportions. capacity At present, 17.9 million people in the United States have III. Role of Mitochondria in Tissue-Specific Contexts been diagnosed with diabetes, with an additional 5.7 mil- A. Muscle lion undiagnosed (1). Together, this encompasses 8% of B. Adipose tissue C. Liver the population, and thus, diabetes is a major public health D. Pancreatic ␤-cells issue. In addition, current data indicate that 57 million IV. Experimental Strategies to Explore the Relationship be- Americans suffer from prediabetes (defined as fasting tween Mitochondrial Function and DM blood glucose between 100 and 125 mg/dl) (1). Diabetes A. PGC-1 ␣ and ␤ overexpression disproportionately affects specific ethnic populations, B. PGC-1 knockout models C. Other mitochondrial function defects with risk increased 1.8-fold in African-Americans, 1.7- V. Conclusions fold in Mexican-Americans, and 2.2-fold in Native Amer- ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BMI, Body mass index; CoA, coenzyme A; COX, cytochrome oxidase; CPT1, Printed in U.S.A. carnitine palmitoylotransferase 1; DM, diabetes mellitus; ERR, estrogen-related receptor; Copyright © 2010 by The Endocrine Society ETC, electron transport chain; FADH2, reduced flavin adenine dinucleotide; MIDD, mater- doi: 10.1210/er.2009-0027 Received July 2, 2009. Accepted December 24, 2009. nally inherited diabetes and deafness; mtDNA, mitochondrial DNA; NADH, reduced nic- First Published Online February 15, 2010 otinamide adenine dinucleotide; NASH, nonalcoholic steatohepatitis; NMR, nuclear mag- netic resonance; NRF, nuclear respiratory factor; OXPHOS, oxidative phosphorylation; PGC, PPAR␥ coactivator; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; RQ, respiratory quotient; TCA, tricarboxylic acid; UCP, uncoupling protein. 364 edrv.endojournals.org Endocrine Reviews, June 2010, 31(3):364–395 Endocrine Reviews, June 2010, 31(3):364–395 edrv.endojournals.org 365 icans. In addition to the major health consequences to glucose disposal during the hyperinsulinemic euglycemic individuals, including higher risk of death, heart disease, clamp or by iv glucose tolerance testing, is common in stroke, kidney disease, blindness, amputations, neuropa- high-risk individuals years before the onset of type 2 DM thy, and pregnancy-related complications, diabetes and its (27–29). However, insulin resistance is not predictive of complications result in a total cost of $174 billion in the diabetes in individuals without a family history of diabe- United States (2). By far, the largest proportion is derived tes, indicating that additional unidentified factors are nec- from type 2 DM, which accounts for more than 90% of essary for disease progression (30). diabetes. Unfortunately, the incidence of diabetes has Multiple mechanisms have recently emerged as poten- more than doubled in the past 25 yr, with 1.6 million new tial causes of insulin resistance and/or diabetes progres- cases diagnosed in adults in 2007 (2) and a projected in- sion, among them impaired mitochondrial capacity crease of 165% from 2000 to 2050 (4). and/or function; altered insulin signaling due to cellular Downloaded from https://academic.oup.com/edrv/article/31/3/364/2354793 by guest on 23 September 2021 Intimately linked with the rise in diabetes prevalence is lipid accumulation, proinflammatory signals, and endo- the burgeoning epidemic of obesity around the world, par- plasmic reticulum stress; and reduced incretin-dependent ticularly in developed societies (5). In 2004, 17% of chil- and -independent ␤-cell insulin secretion. In this review, dren in the United States between ages 2 and 19 yr were we will focus on a critical assessment of the evidence link- overweight, and 32% of adults over age 20 were obese (6). ing mitochondrial function to diabetes pathogenesis, at Both obesity and related inactivity are likely to contribute both a cellular and whole-body level. to the pathogenesis of diabetes because the incidence of diabetes can be reduced by modest weight loss and exercise (7–9). In light of these findings, an important public health II. General Overview of Mitochondrial Biology goal should be to understand the complex pathophysiol- ogy of diabetes and to identify and target specific mech- Mitochondria are double-membrane organelles that serve anisms to prevent DM in at-risk individuals. multiple essential cellular functions (Fig. 1) mediated by thousands of mitochondrial-specific proteins encoded by A. Risk factors associated with type 2 diabetes both the nuclear and mitochondrial genomes (31, 32). Multiple physiological abnormalities can be found in Although mitochondria are most often recognized for individuals with established type 2 DM, defined on the their role in generating the majority of cellular ATP via basis of elevations in fasting and/or postprandial glucose oxidative phosphorylation (OXPHOS), other essential (2). These include insulin resistance in muscle and adipose metabolic functions include the generation by the tricar- tissue, ␤-cell dysfunction leading to impaired insulin se- boxylic acid (TCA) cycle of numerous metabolites that cretion, increased hepatic glucose production, abnormal function in cytosolic pathways, oxidative catabolism of secretion and regulation of incretin hormones, and altered amino acids, ketogenesis, ornithine cycle activity (“urea balance of central nervous system pathways controlling cycle”), the generation of reactive oxygen species (ROS) food intake and energy expenditure. Given this diverse with important signaling functions (33, 34), the control of constellation of abnormalities in multiple tissues and the cytoplasmic calcium (35, 36), and the synthesis of all cel- secondary consequences of established hyperglycemia and lular Fe/S clusters, protein cofactors essential for cellular hyperlipidemia, it is difficult to identify the primary events functions such as protein translation and DNA repair (37). that lead to the development of diabetes. To address this The rate-limiting first step in steroidogenesis also occurs in key clinical and scientific question, it is important not only mitochondria, thus linking mitochondrial function to to determine abnormalities associated with established endocrine homeostasis (38–41). This multiplicity of disease, but also to identify underlying metabolic char- organelle functions explains the variability in patho- acteristics preceding the onset of disease in at-risk physiology, severity, and age of onset of the increasing individuals. number of diseases recognized to arise from primary or Risk factors for the development of and/or progression secondary alterations in specific mitochondrial path- of type 2 DM include: 1) genetics (10–16), exemplified by ways (37, 42–44). the high risk of type 2 DM in particular ethnic groups (17) and the high concordance rates in monozygotic twin