Phielix Esther, Schrauwen-Hinderling Vera B, Mensink Marco, Lenaers Ellen, Meex Ruth, Hoeks Joris, Kooi Marianne Eline, Moonen-Kornips Esther, Sels Jean-Pierre, Hesselink Matthijs K C, Schrauwen Patrick
Department of Human Biology, Maastricht University, Maastricht, the Netherlands.
Diabetes. 2008 Nov;57(11):2943-9. doi: 10.2337/db08-0391. Epub 2008 Aug 4.
A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients.
Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic clamp. Ex vivo intrinsic mitochondrial respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized for mitochondrial content. In vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time after exercise using (31)P-magnetic resonance spectroscopy.
Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 +/- 2.8 vs. 28.9 +/- 3.7 micromol x kg(-1) fat-free mass x min(-1), respectively; P = 0.003), with intermediate values for first-degree relatives (22.1 +/- 3.4 micromol x kg(-1) fat-free mass x min(-1)). In vivo mitochondrial function was 25% lower in diabetic patients (P = 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance (P = 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients (P = 0.031), and fluoro-carbonyl cyanide phenylhydrazone-driven maximal mitochondrial respiratory capacity was 31% lower in diabetic patients (P = 0.05) compared with control subjects with intermediate values for first-degree relatives.
A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity.
据报道，2型糖尿病患者及其一级亲属体内的线粒体功能均较低。这种降低的本质尚不清楚。在此，我们检验了以下假设：内在线粒体呼吸能力较低可能是糖尿病患者体内线粒体功能较低的基础。
10名超重糖尿病男性患者、12名一级亲属男性以及16名年龄和体重指数相匹配的对照男性参与了本研究。采用高胰岛素-正常血糖钳夹技术测量胰岛素敏感性。使用高分辨率呼吸测定法测定透皮骨骼肌纤维中的离体内在线粒体呼吸能力，并根据线粒体含量进行标准化。通过使用（31）P磁共振波谱测量运动后磷酸肌酸恢复半衰期来测定体内线粒体功能。
与对照受试者相比，糖尿病患者胰岛素刺激的葡萄糖处置较低（分别为11.2±2.8与28.9±3.7微摩尔×千克（-1）去脂体重×分钟（-1）；P = 0.003），一级亲属的值处于中间水平（22.1±3.4微摩尔×千克（-1）去脂体重×分钟（-1））。糖尿病患者的体内线粒体功能降低了25%（P = 0.034），一级亲属降低了23%，但后者未达到统计学显著性（P = 0.08）。有趣的是，与对照受试者相比，糖尿病患者的ADP刺激的基础呼吸降低了35%（P = 0.031），氟代羰基氰化物苯腙驱动的最大线粒体呼吸能力降低了31%（P = 0.05），一级亲属的值处于中间水平。
基础ADP刺激的和最大线粒体呼吸能力降低是体内线粒体功能降低的基础，与线粒体含量无关。电子传递链和磷酸化系统水平的能力降低是这种线粒体能力受损的基础。
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