The role of mitochondria in the pathogenesis of type 2 diabetes

Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Endocrine reviews (Impact Factor: 19.36). 02/2010; 31(3):364-95. DOI: 10.1210/er.2009-0027
Source: PubMed

ABSTRACT 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.

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    • "MTP-131 appears to protect the architecture of mitochondrial cristae by reducing mitochondrial oxidative stress and preventing cytochrome c peroxidase activity (Birk et al., 2013; Zhao et al., 2004). Mitochondrial abnormalities have been documented in insulinresistant and diabetic states in human and animal studies, and it has been proposed that mitochondrial dysfunction may be the primary defect in obesity-related insulin resistance (Patti and Corvera, 2010). "
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    Disease Models and Mechanisms 04/2015; DOI:10.1242/dmm.020248 · 5.54 Impact Factor
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    • "Apart from ROS accumulation, dysfunctional mitochondria impair oxidative metabolism (e.g. ATP production, fatty acid and glucose oxidation) provoking increased visceral adiposity, blood glucose and insulin resistance [11] [12]. These metabolic changes are deleterious to organs maintenance. "
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    ABSTRACT: The development of innovative anti-aging strategy is urgently needed to promote healthy aging and overcome the occurrence of age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. Genomic instability, deregulated nutrient sensing and mitochondrial dysfunction are established hallmark of aging. Interestingly, the orphan nuclear receptors NR4A subfamily (NR4A1, NR4A2 and NR4A3) are nutrient sensors that trigger mitochondria biogenesis and improve intrinsic mitochondrial function. In addition, NR4A receptors are components of DNA repair machinery and promote DNA repair. Members of the NR4A subfamily should also be involved in anti-aging properties of hormesis since these receptors are induced by various form of cellular stress and stimulate protective cells response such as anti-oxidative activity and DNA repair. Previous studies reported that NR4A nuclear receptors subfamily is potential therapeutic targets for the treatment of age related disorders (e.g. metabolic syndromes, diabetes and neurodegenerative diseases). Consequently, we propose that targeting NR4A receptors might constitute a new approach to delay aging and the onset of diseases affecting our aging population. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Medical Hypotheses 12/2014; 84(2). DOI:10.1016/j.mehy.2014.12.003 · 1.07 Impact Factor
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    • "The increase in the supply of reducing equivalents (i.e. NADH and FADH 2 ) to the electron transport chain (ETC), without a parallel increase in the oxidative phosphorylation (OXPHOS) capacity, might result in the loss of electrons from the ETC and subsequently, the generation of reactive oxygen species (ROS) [10]. In turn, increased ROS may promote mitochondrial uncoupling [11] [12] [13] [14] [15], as a mechanism to reduce the electrochemical proton gradient required for ROS formation, which will however result in lower ATP generation. "
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