Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle

AIMS/HYPOTHESIS: Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content. MATERIALS AND METHODS: The O(2) flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (n = 8; age 58 ± 2 years [mean±SEM]; BMI 28 ± 1 kg/m(2); fasting plasma glucose 5.4 ± 0.2 mmol/l) and patients with type 2 diabetes (n = 11; age 62 ± 2 years; BMI 32 ± 2 kg/m(2); fasting plasma glucose 9.0 ± 0.8 mmol/l) was measured by high-resolution respirometry. RESULTS: O(2) flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower (p < 0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31 ± 2 vs 43 ± 3 pmol O(2) s(−1) mg(−1)) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63 ± 3 vs 85 ± 6 pmol s(−1) mg(−1)). Further increases in O(2) flux capacity were observed in response to uncoupling by FCCP, but were again lower (p < 0.05) in type 2 diabetic patients than in healthy control subjects (86 ± 4 vs 109 ± 8 pmol s(−1) mg(−1)). However, when O(2) flux was normalised for mitochondrial DNA content or citrate synthase activity, there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects. CONCLUSIONS/INTERPRETATION: Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content

Ceramides: a new player in the inflammation-insulin resistance paradigm?

No abstract available

High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans.

High-fat, low-carbohydrate (CHO) diets increase whole-body rates of fat oxidation and down-regulate CHO metabolism. We measured substrate utilization and skeletal muscle mitochondrial respiration to determine whether these adaptations are driven by high fat or low CHO availability. In a randomized crossover design, 8 male cyclists consumed 5 d of a high-CHO diet [>70% energy intake (EI)], followed by 5 d of either an isoenergetic high-fat (HFAT; >65% EI) or high-protein diet (HPRO; >65% EI) with CHO intake clamped at <20% EI. During the intervention, participants undertook daily exercise training. On d 6, participants consumed a high-CHO diet before performing 100 min of submaximal steady-state cycling plus an ∼30-min time trial. After 5 d of HFAT, skeletal muscle mitochondrial respiration supported by octanoylcarnitine and pyruvate, as well as uncoupled respiration, was decreased at rest, and rates of whole-body fat oxidation were higher during exercise compared with HPRO. After 1 d of high-CHO diet intake, mitochondrial respiration returned to baseline values in HFAT, whereas rates of substrate oxidation returned toward baseline in both conditions. These findings demonstrate that high dietary fat intake, rather than low-CHO intake, contributes to reductions in mitochondrial respiration and increases in whole-body rates of fat oxidation after a consuming a high-fat, low-CHO diet.-Leckey, J. J., Hoffman, N. J., Parr, E. B., Devlin, B. L., Trewin, A. J., Stepto, N. K., Morton, J. P., Burke, L. M., Hawley, J. A. High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans

Ageing, adipose tissue, fatty acids and inflammation

A common feature of ageing is the alteration in tissue distribution and composition, with a shift in fat away from lower body and subcutaneous depots to visceral and ectopic sites. Redistribution of adipose tissue towards an ectopic site can have dramatic effects on metabolic function. In skeletal muscle, increased ectopic adiposity is linked to insulin resistance through lipid mediators such as ceramide or DAG, inhibiting the insulin receptor signalling pathway. Additionally, the risk of developing cardiovascular disease is increased with elevated visceral adipose distribution. In ageing, adipose tissue becomes dysfunctional, with the pathway of differentiation of preadipocytes to mature adipocytes becoming impaired; this results in dysfunctional adipocytes less able to store fat and subsequent fat redistribution to ectopic sites. Low grade systemic inflammation is commonly observed in ageing, and may drive the adipose tissue dysfunction, as proinflammatory cytokines are capable of inhibiting adipocyte differentiation. Beyond increased ectopic adiposity, the effect of impaired adipose tissue function is an elevation in systemic free fatty acids (FFA), a common feature of many metabolic disorders. Saturated fatty acids can be regarded as the most detrimental of FFA, being capable of inducing insulin resistance and inflammation through lipid mediators such as ceramide, which can increase risk of developing atherosclerosis. Elevated FFA, in particular saturated fatty acids, maybe a driving factor for both the increased insulin resistance, cardiovascular disease risk and inflammation in older adults

Reduced skeletal muscle mitochondrial respiration and improved glucose metabolism in nondiabetic obese women during a very low calorie dietary intervention leading to rapid weight loss.

Reduced oxidative capacity of skeletal muscle has been proposed to lead to accumulation of intramyocellular triglyceride (IMTG) and insulin resistance. We have measured mitochondrial respiration before and after a 10% low-calorie-induced weight loss in young obese women to examine the relationship between mitochondrial function, IMTG, and insulin resistance. Nine obese women (age, 32.3 years [SD, 3.0]; body mass index, 33.4 kg/m(2) [SD, 2.6]) completed a 53-day (SE, 3.8) very low calorie diet (VLCD) of 500 to 600 kcal/d without altering physical activity. The target of the intervention was a 10% weight loss; and measurements of mitochondrial respiration, IMTG, respiratory exchange ratio, citrate synthase activity, mitochondrial DNA copy number, plasma insulin, 2-hour oral glucose tolerance test, and free fatty acids were performed before and after weight loss. Mitochondrial respiration was measured in permeabilized muscle fibers using high-resolution respirometry. Average weight loss was 11.5% (P < .05), but the levels of IMTG remained unchanged. Fasting plasma glucose, plasma insulin homeostasis model assessment of insulin resistance, and insulin sensitivity index (composite) obtained during 2-hour oral glucose tolerance test improved significantly. Mitochondrial respiration per milligram tissue decreased by approximately 25% (P < .05), but citrate synthase activity and mitochondrial DNA copy number remained unchanged. Respiratory exchange ratio decreased from 0.87 (SE, 0.01) to 0.79 (SE, 0.02) (P < .05) as a sign of increased whole-body fat oxidation. Markers of insulin sensitivity improved after the very low calorie diet; but mitochondrial function decreased, and IMTG remained unchanged. Our results do not support a direct relationship between mitochondrial function and insulin resistance in young obese women and do not support a direct relationship between IMTG and insulin sensitivity in young obese women during weight loss

Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes?

OBJECTIVE-Chronic exercise and obesity both increase intra-myocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercise-trained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite higher IMTGs and would account for its higher insulin sensitivity. We also hypothesized that the expression of key skeletal muscle proteins involved in lipid droplet hydrolysis, DAG formation, and fatty-acid partitioning and oxidation would be associated with the lipotoxic phenotype.RESEARCH DESIGN AND METHODS-A total of 14 normal-weight, endurance-trained athletes (NWA group) and 7 normal-weight sedentary (NWS group) and 21 obese sedentary (OBS group) volunteers were studied. Insulin sensitivity was assessed by glucose clamps. IMTGs, DAGs, ceramides, and protein expression were measured in muscle biopsies.RESULTS-DAG content in the NWA group was approximately twofold higher than in the OBS group and similar to 50% higher than in the NWS group, corresponding to higher insulin sensitivity. While certain DAG moieties clearly were associated with better insulin sensitivity, other species were not. Ceramide content was higher in insulin-resistant obese muscle. The expression of OXPAT/perilipin-5, adipose triglyceride lipase, and stearoyl-CoA desaturase protein was higher in the NWA group, corresponding to a higher mitochondrial content, proportion of type 1 myocytes, DAGs, and insulin sensitivity.CONCLUSIONS-Total myocellular DAGs were markedly higher in highly trained athletes, corresponding with higher insulin sensitivity, and suggest a more complex role for DAGs in insulin action. Our data also provide additional evidence in humans linking ceramides to insulin resistance. Finally, this study provides novel evidence supporting a role for specific skeletal muscle proteins involved in intramyocellular lipids, mitochondrial oxidative capacity, and insulin resistance. Diabetes 60:2588-2597, 201