Mitochondrial dysfunction and insulin resistance: an update.

), during heightened metabolicdemand (i.e. contraction) there is anessential requirement for rapid andsustained ATP production, a role fulfilledprimarilybymitochondria.Assuch,skeletalmuscle cells are densely populated withthese complex organelles.Withanincreasingprevalenceofinactivityand obesity, type 2 diabetes has become amajor public health concern. Given theircentral role in energy production, it isperhaps not surprising that mitochondrialdysfunction has been implicated inthe aetiology of skeletal muscle insulinresistance, a precursor of frank diabetes.Furthermore,interventionswhichstimulateskeletal muscle mitochondrial biogenesiscan improve insulin sensitivity in obeseand/or insulin resistant individuals. Whileit seems clear that a reduction inskeletal muscle mitochondrial

Do mitochondria care about insulin resistance?

Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance

Antiretroviral nucleoside and nucleotide analogues and mitochondria.

Editorial (Thematic Issue: Mitochondrial Biogenesis: Pharmacological Approaches)

Mitochondrial dysfunction has been suggested to play a significant role in obesity and insulin resistance. The aim of the present study was to investigate if changes in obesity and insulin resistance were related to similar changes in mitochondrial capacity for hydrogen peroxide release in Zucker diabetic fatty rats and their lean littermates. Thirty-four rats were used in this study. Rats were either lean or obese Zucker rats killed at 5-6 (young) or 12-14 (adults) weeks of age. Mitochondria were isolated from soleus muscles; respiration and release of hydrogen peroxide were determined and related to citrate synthase activity to determine intrinsic mitochondrial function. Mitochondrial-specific super-oxide dismuthase (MnSOD) protein content was determined in isolated mitochondria and muscle homogenate. Catalase protein content was determined in muscle homogenate. Young lean and obese rats had a higher mitochondrial respiration when using palmitoyl-l-carnitine as substrate compared with adult lean and obese rats. The obese strain had higher mitochondrial hydrogen peroxide release but only in the adult animals. In both lean and obese animals, increased age was associated with increased mitochondrial hydrogen peroxide release. MnSOD tended to be higher in the obese strain in the isolated mitochondria. Regardless of age, catalase protein content was significantly lower in the obese rats. This study shows that the augmented increase in obesity and insulin resistance seen in Zucker diabetic fatty rats is associated with increased capacity for mitochondrial hydrogen peroxide release.

Epidemiological studies suggest that chronic consumption of trans MUFA may alter muscle insulin sensitivity. The major sources of dietary trans MUFA (dairy fat vs. industrially hydrogenated oils) have different isomeric profiles and thus probably different metabolic consequences. These effects may involve alterations in muscle mitochondrial oxidative capacity, which may in turn promote insulin resistance if fatty acid oxidation is reduced. We report that in Wistar rats, an 8 week diet enriched (4% of energy intake) in either dairy, industrial, or control MUFA did not alter insulin and glucose responses to an intraperitoneal glucose tolerance test (1g/kg). In C2C12 myotubes, vaccenic and elaidic acids did not modify insulin sensitivity compared with oleic acid. Furthermore, the ex vivo total, mitochondrial and peroxisomal oxidation rates of [1-(14)C]oleic, vaccenic, and elaidic acids were similar in soleus and tibialis anterior rat muscle. Finally, an 8 week diet enriched in either dairy or industrial trans MUFA did not alter mitochondrial oxidative capacity in these two muscles compared with control MUFA but did induce a specific reduction in soleus mitochondrial ATP and superoxide anion production (P<0.01 vs. control). In conclusion, dietary trans MUFA of dairy or industrial origin have similar effects and do not impair muscle mitochondrial capacity and insulin sensitivity.

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity

Systems biology of energy metabolism in skeletal muscle

There is equivocal evidence of in utero nucleoside reverse transcriptase inhibitor (NRTI) exposure and the occurrence of mitochondrial dysfunction (MD) in HIV-uninfected children born of HIV-infected women. The primary analysis included 1037 HIV-uninfected children born in 1991-2002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C. Possible cases with unexplained signs of MD according to the Enquête Périnatale Française criteria were identified through retrospective review. Associations between overall in utero NRTI exposure, and trimester of first in utero NRTI exposure and possible MD were estimated with exact logistic regression. Cases (n = 20) were significantly more likely to be male and to be born in earlier years than non-cases (n = 1017). There was no association between overall in utero NRTI exposure and MD. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) [odds ratio (OR), 3.76 versus 3TC unexposed; 95% confidence interval (CI), 1.09-11.78] and to zidovudine (ZDV) and 3TC in combination (ZDV/3TC) (OR, 3.29 vs. ZDV/3TC unexposed; 95% CI, 0.96-10.25) among cases than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC (OR, 10.57; 95% CI, 1.93-75.61) and ZDV/3TC (OR, 9.84; 95% CI, 1.77-71.68) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use. Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed.

The evolving role of mitochondria in metabolism

No need to sweat: is dieting enough to alleviate insulin resistance in obesity?

Series introduction: the molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular diseases.

Physical inactivity reduces, and exercise training increases, mitochondrial capacity. In rodents, exercise training effects can be augmented by large doses of resveratrol supplementation but whether this can occur in humans with a smaller dose is unclear. This study sought to determine the effects of resveratrol supplementation in combination with exercise training on skeletal muscle mitochondrial capacity. Sixteen healthy young adults were randomly assigned in a double-blind fashion to consume either placebo or 500 mg of resveratrol plus 10 mg of piperine, a bioenhancer to increase bioavailibilty and bioefficacy of resveratrol. Participants ingested the pills daily for 4 weeks and completed 3 sessions per week of submaximal endurance training of the wrist flexor muscles of the nondominant arm. The contralateral arm served as an untrained control. Skeletal muscle mitochondrial capacity was measured using near-infrared spectroscopy. Changes in mitochondrial capacity from baseline to post-testing indicated significant differences between the resveratrol+piperine-trained arm and the placebo-trained arm (p = 0.02), with the resveratrol+piperine group increasing about 40% from baseline (Δk = 0.58), while the placebo group increased about 10% from baseline (Δk = 0.13). Neither the placebo group nor the resveratrol+piperine group exhibited changes in mitochondrial capacity in the untrained arm. In conclusion, low-intensity exercise training can increase forearm skeletal muscle mitochondrial capacity when combined with resveratrol and piperine supplementation.

Changes in mitochondrial capacity and quality play a critical role in skeletal and cardiac muscle dysfunction. In vivo measurements of mitochondrial capacity provide a clear link between physical activity and mitochondrial function in aging and heart failure, although the cause and effect relationship remains unclear. Age-related decline in mitochondrial quality leads to mitochondrial defects that affect redox, calcium, and energy-sensitive signaling by altering the cellular environment that can result in skeletal muscle dysfunction independent of reduced mitochondrial capacity. This reduced mitochondrial quality with age is also likely to sensitize skeletal muscle mitochondria to elevated angiotensin or beta-adrenergic signaling associated with heart failure. This synergy between aging and heart failure could further disrupt cell energy and redox homeostasis and contribute to exercise intolerance in this patient population. Therefore, the interaction between aging and heart failure, particularly with respect to mitochondrial dysfunction, should be a consideration when developing strategies to improve quality of life in heart failure patients. Given the central role of the mitochondria in skeletal and cardiac muscle dysfunction, mitochondrial quality may provide a common link for targeted interventions in these populations.