The role of mitochondria in insulin resistance and type 2 diabetes mellitus

Abstract

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.

Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes

“…On the other hand, maximal oxygen uptake (V : O 2max ) during exhaustive physical activity corresponds to muscle mitochondrial oxidative capacity, as reflected by ADP-stimulated oxidative phosphorylation at submaximal energy demand during exercise [2]. Whether the impaired metabolic flexibility in type 2 diabetes results from disturbed mitochondrial oxidation rather than from diminished muscle glucose uptake is as yet unclear.…”

“…The latter comprise excess lipid availability with activation of the diacylglycerol-protein kinase C pathway [1] abnormalities in mitochondrial function [2] and glucose toxicity, at least in individuals with overt type 2 diabetes mellitus.…”

Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells

“…Moreover, mitochondria are essential for oxidative metabolism in eukaryotic cells and represent the major contributor to energy transduction and ATP production. Not surprisingly, mitochondrial dysfunction has been associated with various diseases including metabolic disorders, neurodegenerative diseases, and cancer (1)(2)(3)(4)(5)(6)(7). In mitochondria, virtually all metabolic processes depend on NAD.…”

Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

“…The association of low testosterone with insulin resistance and reduced muscle mass suggests that common factors may play a role in these metabolic disorders in men. In aging, obesity, and type 2 diabetes, insulin resistance in skeletal muscle has been linked to a number of abnormalities in mitochondrial oxidative metabolism (7,8,9,10). This includes transcriptomic and proteomic evidence of a coordinated downregulation of genes and proteins involved in oxidative phosphorylation (OxPhos) in insulin-resistant skeletal muscle (11,12,13,14) as well as reduced expression of the peroxisome proliferatoractivated receptor gamma coactivator 1 alpha gene (PGC1a), which plays a key role in mitochondrial biogenesis (13,14).…”