AIMS/HYPOTHESIS:Impaired regulation of lipolysis and accumulation of lipid intermediates may contribute to obesity-related insulin resistance and type 2 diabetes mellitus. We investigated insulin-mediated suppression of lipolysis in abdominal subcutaneous adipose tissue (AT) and skeletal muscle (SM) of obese men with normal glucose tolerance (NGT) and obese type 2 diabetic men. METHODS:Eleven NGT men and nine long-term diagnosed type 2 diabetic men (7 ± 1 years), matched for age (58 ± 2 vs 62 ± 2 years), BMI (31.4 ± 0.6 vs 30.5 ± 0.6 kg/m(2)) and [Formula: see text] (28.9 ± 1.5 vs 29.5 ± 2.4 ml kg(-1) min(-1)) participated in this study. Interstitial glycerol concentrations in AT and SM were assessed using microdialysis during a 1 h basal period and a 6 h stepwise hyperinsulinaemic-euglycaemic clamp (8, 20 and 40 mU m(-2) min(-1)). AT and SM biopsies were collected to investigate underlying mechanisms. RESULTS:Hyperinsulinaemia suppressed interstitial SM glycerol concentrations less in men with type 2 diabetes (-7 ± 6%, -13 ± 9% and -27 ± 9%) compared with men with NGT (-21 ± 7%, -38 ± 8% and -53 ± 8%) (p = 0.014). This was accompanied by increased circulating fatty acid and glycerol concentrations, a lower glucose infusion rate (21.8 ± 3.1 vs 30.5 ± 2.0 μmol kg body weight(-1) min(-1); p < 0.05), higher hormone-sensitive lipase (HSL) serine 660 phosphorylation, increased saturated diacylglycerol (DAG) lipid species in the muscle membrane and increased protein kinase C (PKC) activation in type 2 diabetic men vs men with NGT. No significant differences in insulin-mediated reduction in AT interstitial glycerol were observed between groups. CONCLUSIONS/INTERPRETATION:Our results suggest that a blunted insulin-mediated suppression of SM lipolysis may promote the accumulation of membrane saturated DAG, aggravating insulin resistance, at least partly mediated by PKC. This may represent an important mechanism involved in the progression of insulin resistance towards type 2 diabetes. TRIAL REGISTRATION:ClinicalTrials.gov NCT01680133.

译文

目的/假设:脂解作用的调节受损和脂质中间体的积累可能会导致肥胖相关的胰岛素抵抗和2型糖尿病。我们调查了胰岛素抵抗正常的肥胖男性和2型糖尿病男性肥胖者的腹部皮下脂肪组织(AT)和骨骼肌(SM)的胰岛素介导的脂解抑制作用。
方法:11名NGT男性和9名经长期诊断的2型糖尿病男性(7±1岁),年龄相匹配(58±2 vs 62±2岁),BMI(31.4±0.6 vs 30.5±0.6 kg / m(2) )和[公式:参见文字](28.9±1.5 vs 29.5±2.4 ml kg(-1)min(-1))参与了这项研究。在1 h的基础期和6 h的逐步高胰岛素血症-正常血糖钳制(8、20和40 mU m(-2)min(-1))中使用微透析法评估AT和SM中的间质甘油浓度。收集AT和SM活组织检查以研究潜在的机制。
结果:与NGT男性(-21±7%,-38±8)相比,高胰岛素血症抑制的2型糖尿病男性的间质SM甘油浓度更低(-7±6%,-13±9%和-27±9%) %和-53±8%)(p = 0.014)。这伴随着循环脂肪酸和甘油浓度的增加,葡萄糖输注速率的降低(21.8±3.1 vs 30.5±2.0μmolkg体重(-1)min(-1); p <0.05),激素敏感性脂肪酶更高( HSL)丝氨酸660磷酸化,2型糖尿病男性患者与NGT男性相比,肌肉膜中饱和二酰基甘油(DAG)脂质种类增加,蛋白激酶C(PKC)活化增加。两组之间在胰岛素介导的AT间质甘油减少方面没有观察到显着差异。
结论/解释:我们的结果表明,胰岛素介导的SM脂解抑制作用减弱可能会促进膜饱和DAG的积累,加重胰岛素抵抗,至少部分是由PKC介导的。这可能代表了胰岛素抵抗向2型糖尿病发展的重要机制。
试用注册:ClinicalTrials.gov NCT01680133。

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