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Aims/hypothesis: Physical inactivity, low mitochondrial function, increased intramyocellular lipid (IMCL) deposition and reduced insulin sensitivity are common denominators of chronic metabolic disorders, like obesity and type 2 diabetes. Yet, whether low mitochondrial function predisposes to insulin resistance in humans is still unknown. Methods: Here we investigated, in an intervention study, whether muscle with low mitochondrial oxidative capacity, induced by one-legged physical inactivity, would feature stronger signs of lipid-induced insulin resistance. To this end, ten male participants (age 22.4 ± 4.2 years, BMI 21.3 ± 2.0 kg/m2) underwent a 12 day unilateral lower-limb suspension with the contralateral leg serving as an active internal control. Results: In vivo, mitochondrial oxidative capacity, assessed by phosphocreatine (PCr)-recovery half-time, was lower in the inactive vs active leg. Ex vivo, palmitate oxidation to 14CO2 was lower in the suspended leg vs the active leg; however, this did not result in significantly higher [14C]palmitate incorporation into triacylglycerol. The reduced mitochondrial function in the suspended leg was, however, paralleled by augmented IMCL content in both musculus tibialis anterior and musculus vastus lateralis, and by increased membrane bound protein kinase C (PKC) θ. Finally, upon lipid infusion, insulin signalling was lower in the suspended vs active leg. Conclusions/interpretation: Together, these results demonstrate, in a unique human in vivo model, that a low mitochondrial oxidative capacity due to physical inactivity directly impacts IMCL accumulation and PKCθ translocation, resulting in impaired insulin signalling upon lipid infusion. This demonstrates the importance of mitochondrial oxidative capacity and muscle fat accumulation in the development of insulin resistance in humans. Trial registration: ClinicalTrial.gov NCT01576250. Funding: PS was supported by a 'VICI' Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 918.96.618). [ABSTRACT FROM AUTHOR]

Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and 1 H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFα (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways. [ABSTRACT FROM AUTHOR]

Objective The purpose of the present study was to examine the effects of 3 days isoenergetic high-fat/low-carbohydrate diet (HF-LC) relative to low-fat/high-carbohydrate diet (LF-HC) on the exercise-induced growth hormone (GH) response in healthy male subjects. Design Ten healthy young males participated in this study. Each subject consumed the HF-LC (18 ± 1% protein, 61 ± 2% fat, 21 ± 1% carbohydrate, 2720 kcal per day) for 3 consecutive days after consuming the LF-HC (18 ± 1% protein, 20 ± 1% fat, 62 ± 1% carbohydrate, 2755 kcal per day) for 3 consecutive days. After each dietary intervention period, the hormonal and metabolic responses to an acute exercise (30 min of continuous pedaling at 60% of V ˙ O 2max ) were compared. The intramyocellular lipid (IMCL) contents in the vastus lateralis, soleus, and tibialis anterior were evaluated by proton magnetic resonance spectroscopy. Results Serum GH concentrations increased significantly during the exercise after both the HF-LC and LF-HC periods ( P < 0.05). However, the exercise-induced GH response was not significantly different between the two periods. Fat utilization and lipolytic responses during the exercise were enhanced significantly after the HF-LC period compared with the LF-HC period. IMCL content did not differ significantly in any portion of muscle after the dietary interventions. Conclusions We could not show that short-term HF-LC consumption changed significantly exercise-induced GH response or IMCL content in healthy young males. [ABSTRACT FROM AUTHOR]

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The present study was conducted to determine change in regional fat accumulation and appetite-related hormonal response following hypoxic training. Twenty sedentary subjects underwent hypoxic ( n = 9, HYPO, FiO2 = 15%) or normoxic training ( n = 11, NOR, FiO2 = 20·9%) during a 4-week period (3 days per week). They performed a 4-week training at 55% of maximal oxygen uptake ( [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Intramyocellular lipid accumulation and insulin resistance are thought to be due to reduced lipid oxidation in a human model of high risk of developing type 2 diabetes. Methods: We studied 32 off- spring of type 2 diabetic parents and 32 control individuals by means of DXA, indirect calorimetry, insulin clamp and 1H MRS of the calf muscles, and differences between and within study groups were analysed before and after segregation by quartiles of fasting lipid oxidation. Results: In comparison with control subjects, the offspring showed impaired insulin sensitivity, which was associated with higher fasting intramyocellular lipid content (Spearman's rho -O .35;p=O .04), but fasting lipid oxidation did not differ between groups (1.21±0.46 vs. 1.25±0.37 mgkg1 lean body mass per mm; p=O.70). Nevertheless, offspring in the lowest quartile of lipid oxidation had the most severe impairment of insulin sensitivity and a strong association was shown between lipid oxidation and insulin sensitivity within quartiles (Spearman's rho 0.47; p=O.Ol); this was not observed within the control group (Spearman's rho 0.13; p=047). Intramyocellular lipid content was not significantly different within quartiles of lipid oxidation in either of the groups. Conclusions/interpretation: Insulin sensitivity improved across increasing quartiles of fasting lipid oxidation in the offspring group, but remained constant in the control group, supporting the hypothesis that impaired fat oxidation is a primary pathogenic factor of insulin resistance in people with a genetic background for type 2 diabetes. Despite their association with impaired insulin sensitivity, soleus and tibialis anterior intramyo cellular lipid content remained constant across increasing quartiles of fasting lipid oxidation within both groups. [ABSTRACT FROM AUTHOR]

Background: Exaggerated insulin resistance was described as the major metabolic abnormality in myotonic dystrophy type 1 (DM1). We reported recently that the severity of the impairment in insulinstimulated glucose metabolism in these patients was overestimated. Objective: The aim was to dissect out insulin action with respect to whole-body energy homeostasis and glucose, protein, and lipid metabolism in patients withDM1to assess the relevance of insulin resistance to the heterogeneous clinical manifestations of this syndrome. Design: Ten nondiabetic patients withDM1and 10 matched healthy control subjects were studied by means of 1) dual-energy X-ray absorptiometry; 2) a euglycemic-hyperinsulinemic clamp (40 mU . m-2 . min-1) combined with a primed, continuous infusion of [6,6-d2]glucose and [1-13C]leucine; 3) indirect calorimetry; and 4) localized 1H magnetic resonance spectroscopy of the calf muscles. Results: Patients with DM1 had less lean body mass, greater fat mass, and greater intramyocellular lipid contents than did healthy control subjects. Energy expenditure and glucose and lipid metabolism did not differ significantly between the groups. In contrast, markers of proteolysis were higher in DM1 patients in the postabsorptive and insulin-stimulated conditions and were associated with lower plasma concentrations of insulin-like growth factor 1 (P < 0.03) and higher plasma concentrations of tumor necrosis factor α receptor 2 (P = 0.04). Conclusions: Despite greater body fat and intramyocellular lipid contents in patients with DM1, insulin sensitivity was not significantly different between patients and control subjects. In contrast, the loss of lean body mass in patients with DM1 was associated with abnormal postabsorptive and insulin-stimulated regulation of protein breakdown. Lower plasma insulin-like growth factor 1 concentrations and higher tumor necrosis factor system activity might be involved in the muscle wasting of DM1. [ABSTRACT FROM AUTHOR]