Mitochondrial Function and Diabetes: Consequences for Skeletal and Cardiac Muscle Metabolism

SIGNIFICANCE: An early hallmark in the development of type 2 diabetes is the resistance to the effect of insulin in skeletal muscle and in the heart. Since mitochondrial function was found to be diminished in patients with type 2 diabetes, it was suggested that this defect might be involved in the etiology of insulin resistance. Although several hypotheses were suggested, yet unclear is the mechanistic link between these two phenomena. Recent advances: Herein, we review the evidence for disturbances in mitochondrial function in skeletal muscle and the heart in the diabetic state. Also the mechanisms involved in improving mitochondrial function are considered and, whenever possible, human data is cited. Reported evidence shows that interventions that improve skeletal muscle mitochondrial function also improve insulin sensitivity in humans. In the heart, available data from animal studies suggests that enhancement of mitochondrial function can reverse aging-induced changes in heart function, and can be protective against cardiomyopathy and heart failure. FUTURE DIRECTIONS: Mitochondria and their functions can be targeted with the aim of improving skeletal muscle insulin sensitivity and cardiac function. However, human clinical intervention studies are needed to fully substantiate the potential of mitochondria as a target to prevent cardiometabolic disease

The journey of resveratrol from yeast to human

The natural polyphenolic compound resveratrol was first discovered in the 1940s. In the recent years, this compound received renewed interest as several findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction, and regulating longevity in lower organisms. Given the worldwide increase in age-related metabolic diseases the beneficial effects of resveratrol on metabolism and healthy aging in humans are currently a topic of intense investigation

Ticking for Metabolic Health:The Skeletal-Muscle Clocks

To be prepared for alternating metabolic demands occurring over the 24-hour day, the body preserves information on time in skeletal muscle, and all cells, through a circadian clock mechanism. Skeletal muscle can be considered the largest collection of peripheral clocks in the body with a major contribution to whole body energy metabolism. Comparison of circadian clock gene expression between skeletal muscle of nocturnal rodents and diurnal humans reveals very common patterns based on rest/active cycles rather than light/dark cycles. Rodent studies in which the circadian clock is disrupted in skeletal muscle demonstrate impaired glucose handling and insulin resistance. Experimental circadian misalignment in humans modifies the skeletal muscle clocks and leads to disturbed energy metabolism and insulin resistance. Preclinical studies have revealed that timing of exercise over the day can influence the beneficial effects of exercise on skeletal muscle metabolism and studies suggest similar applicability in humans. Current strategies to improve metabolic health, e.g. exercise, should be reinvestigated in their capability to modify the skeletal muscle clocks by taking timing of the intervention into account

Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial

Item does not contain fulltextOBJECTIVE: To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care. RESEARCH DESIGN AND METHODS: Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique. RESULTS: Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction. CONCLUSIONS: Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes.1 december 201