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.

OBJECTIVE-A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients.RESEARCH DESIGN AND METHODS-Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic clamp. Ex vivo intrinsic mitochondrial respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized for mitochondrial content. In vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time after exercise using 31 P-magnetic resonance spectroscopy.RESULTS-Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 Ϯ 2.8 vs. 28.9 Ϯ 3.7 mol ⅐ kg Ϫ1 fat-free mass ⅐ min Ϫ1 , respectively; P ϭ 0.003), with intermediate values for first-degree relatives (22.1 Ϯ 3.4 mol ⅐ kg Ϫ1 fat-free mass ⅐ min Ϫ1 ). In vivo mitochondrial function was 25% lower in diabetic patients (P ϭ 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance (P ϭ 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients (P ϭ 0.031), and fluoro-carbonyl cyanide phenylhydrazone-driven maximal mitochondrial respiratory capacity was 31% lower in diabetic patients (P ϭ 0.05) compared with control subjects with intermediate values for first-degree relatives.CONCLUSIONS-A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity.

Muscle insulin resistance is a key feature of obesity and type 2 diabetes and is strongly associated with increased intramyocellular lipid content and inflammation. However, the cellular and molecular mechanisms responsible for causing muscle insulin resistance in humans are still unclear. To address this question, we performed serial muscle biopsies in healthy, lean subjects before and during a lipid infusion to induce acute muscle insulin resistance and assessed lipid and inflammatory parameters that have been previously implicated in causing muscle insulin resistance. We found that acute induction of muscle insulin resistance was associated with a transient increase in total and cytosolic diacylglycerol (DAG) content that was temporally associated with protein kinase (PKC)θ activation, increased insulin receptor substrate (IRS)-1 serine 1101 phosphorylation, and inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation and AKT2 phosphorylation. In contrast, there were no associations between insulin resistance and alterations in muscle ceramide, acylcarnitine content, or adipocytokines (interleukin-6, adiponectin, retinol-binding protein 4) or soluble intercellular adhesion molecule-1. Similar associations between muscle DAG content, PKCθ activation, and muscle insulin resistance were observed in healthy insulin-resistant obese subjects and obese type 2 diabetic subjects. Taken together, these data support a key role for DAG activation of PKCθ in the pathogenesis of lipid-induced muscle insulin resistance in obese and type 2 diabetic individuals.lipotoxicity | insulin signaling