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.
"This newly discovered ''plasticity'' of adipocytes has intensified efforts to identify novel methods to treat obesity and insulin resistance by increasing browning and peripheral energy expenditure (Boss and Farmer, 2012; Cypess and Kahn, 2010). Mitochondrial dysfunction has been shown to be associated with the development of obesity and insulin resistance (Bournat and Brown, 2010; Patti and Corvera, 2010). The peroxisome proliferator-activated receptor g coactivator-1a (PGC-1a) is a central transcriptional regulator of mitochondrial and peroxisomal remodeling and biogenesis (Wu et al., 1999; Bagattin et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Altering the balance between energy intake and expenditure is a potential strategy for treating obesity and metabolic syndrome. Nonetheless, despite years of progress in identifying diverse molecular targets, biological-based therapies are limited. Here we demonstrate that heat shock factor 1 (HSF1) regulates energy expenditure through activation of a PGC1α-dependent metabolic program in adipose tissues and muscle. Genetic modulation of HSF1 levels altered white fat remodeling and thermogenesis, and pharmacological activation of HSF1 via celastrol was associated with enhanced energy expenditure, increased mitochondrial function in fat and muscle and protection against obesity, insulin resistance, and hepatic steatosis during high-fat diet regimens. The beneficial metabolic changes elicited by celastrol were abrogated in HSF1 knockout mice. Overall, our findings identify the temperature sensor HSF1 as a regulator of energy metabolism and demonstrate that augmenting HSF1 via celastrol represents a possible therapeutic strategy to treat obesity and its myriad metabolic consequences.
"Several mechanisms have been proposed to link the defects in mitochondrial function with insulin resistance (Patti and Corvera 2010; Shulman 2004). The most well-studied model is centred on the uncoupling of mitochondrial fatty acid oxidation and the synthesis of fatty acid-derived metabolites, which may induce a form of toxicity within the myocyte (Schrauwen and Hesselink 2004; Szendroedi and Roden 2008). "
[Show abstract][Hide abstract] ABSTRACT: The prevalence of type 2 diabetes (T2D) has increased dramatically over the past two decades, not only among adults but also among adolescents. T2D is a systemic disorder affecting every organ system and is especially damaging to the cardiovascular system, predisposing individuals to severe cardiac and vascular complications. The precise mechanisms that cause T2D are an area of active research. Most current theories suggest that the process begins with peripheral insulin resistance that precedes failure of the pancreatic β-cells to secrete sufficient insulin to maintain normoglycemia. A growing body of literature has highlighted multiple aspects of mitochondrial function, including oxidative phosphorylation, lipid homeostasis, and mitochondrial quality control in the regulation of peripheral insulin sensitivity. Whether the cellular mechanisms of insulin resistance in adults are comparable to that in adolescents remains unclear. This review will summarize both clinical and basic studies that shed light on how alterations in skeletal muscle mitochondrial function contribute to whole body insulin resistance and will discuss the evidence supporting high-intensity exercise training as a therapy to circumvent skeletal muscle mitochondrial dysfunction to restore insulin sensitivity in both adults and adolescents.
Biochemistry and Cell Biology 05/2015; DOI:10.1139/bcb-2015-0012 · 2.15 Impact Factor
"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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