Type 2 diabetes mellitus (T2DM) has been related to alterations of oxidative metabolism in insulin-responsive tissues. Overt T2DM can present with acquired or inherited reductions of mitochondrial oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and plasticity of mitochondria and/or lower mitochondrial content in skeletal muscle cells and potentially also in hepatocytes. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as the result of blunted mitochondrial plasticity. Hereditary insulin resistance is frequently associated with reduced mitochondrial activity at rest, probably due to diminished mitochondrial content. Lifestyle and pharmacological interventions can enhance the capacity for oxidative phosphorylation and mitochondrial content and improve insulin resistance in some (pre)diabetic cases. Various mitochondrial features can be abnormal but are not necessarily responsible for all forms of insulin resistance. Nevertheless, mitochondrial abnormalities might accelerate progression of insulin resistance and subsequent organ dysfunction via increased production of reactive oxygen species. This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity.
Overt type 2 diabetes mellitus is associated with reduced oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and mitochondrial plasticity in insulin-responsive tissues
Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial plasticity that results in the inability of the organism to switch from fatty acid to glucose oxidation in skeletal muscle
Hereditary insulin resistance can be linked to reduced resting mitochondrial activity at least partly due to a decreased mitochondrial content
Lifestyle and pharmacological interventions can enhance oxidative phosphorylation capacity and mitochondrial content, and in most cases improve insulin resistance in (pre)diabetic states
Reduced oxidative phosphorylation capacity is unlikely to be the general cause of all forms of insulin resistance but might accelerate its progression and subsequent organ dysfunction via increased production of reactive oxygen species
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M. Roden declares an association with the following company: Takeda (consultant). The other authors declare no competing interests.
Cellular processes in insulin-responsive tissues. a. In the fasting state, glucose uptake into insulin-responsive tissues decreases and fuel selection switches from glucose to lipid oxidation (metabolic flexibility). Substrate availability and energy demand are low. b. The insulin-resistant state is characterized by the inability to adapt ATP synthetic flux rates (fATP) to substrate availability; lipid oxidation rates are, therefore, not increased adequately. Lipid metabolites (Acyl-CoA, DAG, ceramides) increase and TG accumulate. Mitochondrial plasticity, for example metabolic flexibility, is the limiting factor for in vivo ATP synthetic rates in insulin-resistant humans. c. During hyperinsulinemia, glucose uptake increases in insulin-responsive tissues, fuel selection switches from lipid to glucose oxidation (metabolic flexibility). In the insulin-stimulated state, energy demand is high and ATP synthetic flux rate is increased. d. In the insulin-resistant state, glucose transport and phosphorylation is reduced and lipid oxidation rates are not decreased adequately. DAG and ceramides induce insulin resistance. Abbreviations: DAG, diacylglycerol; FFA, free fatty acids; GLUT, glucose transporter; IR, insulin receptor; IRS, insulin receptor substrate; TCA, tricarboxylic acid; TG, triglycerides. (PPT 139 kb)
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Szendroedi, J., Phielix, E. & Roden, M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 8, 92–103 (2012). https://doi.org/10.1038/nrendo.2011.138
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