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

Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes

Non-alcoholic fatty liver (NAFL) is an independent risk factor for the development of type 2 diabetes (T2DM). We examined metabolic perturbations in patients with NAFL, patients with T2DM, and control (CON) subjects with normal intrahepatic lipid (IHL) content. A two-step (10 mU/m2 /min; 40 mU/m2/min) hyperinsulinemic–euglycemic clamp was performed in 11 NAFL, 13 T2DM, and 11 CON subjects, all matched for BMI, and aerobic fitness. IHL content was measured using proton magnetic resonance spectroscopy. Because of high IHL content variability in T2DM patients, this group was separated into a high IHL content group (IHL ≥ 5.0%, T2DM+NAFL) and a normal IHL content group (IHL &amp;lt; 5.0%, T2DM-non-NAFL) for further analysis. IHL content was increased in NAFL and T2DM+NAFL subjects (P&amp;lt;0.050 versus CON and T2DM-non-NAFL subjects). Adipose tissue insulin sensitivity index (Adipo-IRi) was higher in NAFL (P&amp;lt;0.050 versus CON and T2DM-non-NAFL subjects) and in T2DM+NAFL subjects (P=0.055 versus CON subjects, P&amp;lt;0.050 versus T2DM-non-NAFL subjects). Suppression of plasma-free fatty acids (P=0.046) was lower in NAFL compared with CON subjects, with intermediate values for T2DM-non-NAFL, and T2DM+NAFL subjects. Suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disposal (ΔRd) was comparable between NAFL, T2DM-non-NAFL, and T2DM+NAFL subjects (all P&amp;gt;0.05), and was lower in comparison with CON subjects (all P&amp;lt;0.01). Metabolic flexibility was lower in T2DM-non-NAFL subjects (P=0.047) and NAFL subjects (P=0.059) compared with CON subjects. Adipo-IRi (r=0.652, P&amp;lt;0.001), hepatic insulin resistance index (HIRi) (r=0.576, P=0.001), and ΔRd (r=−0.653, P&amp;lt;0.001) correlated with IHL content. Individuals with NAFL suffer from metabolic perturbations to a similar degree as T2DM patients. NAFL is an important feature leading to severe insulin resistance and should be viewed as a serious health threat for the development of T2DM. ClinicalTrials.gov: NCT01317576</jats:p