Hernández-Alvarez M I, Chiellini C, Manco M, Naon D, Liesa M, Palacín M, Mingrone G, Zorzano A
Institute for Research in Biomedicine, Parc Cientific de Barcelona, 08028 Barcelona, Spain.
Diabetologia. 2009 Aug;52(8):1618-27. doi: 10.1007/s00125-009-1403-y. Epub 2009 Jun 6.
AIMS/HYPOTHESIS: The mechanisms allowing normalisation of insulin sensitivity and reversal of type 2 diabetes after bilio-pancreatic diversion (BPD) have not been elucidated. We studied whether the expression of genes relevant to mitochondrial biogenesis/function is induced in response to BPD and whether the response differs between morbidly obese patients with normal glucose tolerance (NGT) and patients with type 2 diabetes.
The effect of stable weight reduction after BPD on metabolic variables and expression of nuclear genes encoding for mitochondrial proteins or regulators of mitochondrial function was investigated in skeletal muscle. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and substrate oxidation by indirect calorimetry.
Both NGT and type 2 diabetic patients showed a net improvement of insulin sensitivity, with the latter also showing blood glucose normalisation. NGT patients had a large increase in glucose oxidation and substantial reduction in lipid oxidation. In contrast, type 2 diabetic patients had a blunted response to BPD in terms of glucose oxidation. NGT patients showed increased expression of genes encoding mitofusin 2, porin or citrate synthase; no significant changes were detected in diabetic patients. The expression of genes regulating mitochondrial activity (PGC-1beta [also known as PPARGC1B], PGC-1alpha [also known as PPARGC1A], PPARdelta [also known as PPARD], SIRT1) was induced only in NGT patients.
CONCLUSIONS/INTERPRETATION: These findings indicate that weight loss after BPD exerts a beneficial effect on insulin sensitivity via mechanisms that are independent of the expression of genes involved in mitochondrial biogenesis/activity. Furthermore, the observation that gene expression is not altered with weight loss in type 2 diabetic patients while it is induced in NGT patients suggests a heritable component.
目的/假设：胆胰分流术（BPD）后胰岛素敏感性恢复正常及2型糖尿病逆转的机制尚未阐明。我们研究了与线粒体生物发生/功能相关的基因表达是否因BPD而被诱导，以及糖耐量正常（NGT）的病态肥胖患者与2型糖尿病患者之间的反应是否存在差异。
在骨骼肌中研究BPD后体重稳定减轻对代谢变量以及编码线粒体蛋白或线粒体功能调节因子的核基因表达的影响。通过正常血糖-高胰岛素钳夹技术评估胰岛素敏感性，通过间接量热法评估底物氧化。
NGT患者和2型糖尿病患者的胰岛素敏感性均有净改善，后者还实现了血糖正常化。NGT患者的葡萄糖氧化大幅增加，脂质氧化显著减少。相比之下，2型糖尿病患者在葡萄糖氧化方面对BPD的反应减弱。NGT患者中编码线粒体融合蛋白2、孔蛋白或柠檬酸合酶的基因表达增加；糖尿病患者未检测到显著变化。仅在NGT患者中诱导了调节线粒体活性的基因（PGC-1β [也称为PPARGC1B]、PGC-1α [也称为PPARGC1A]、PPARδ [也称为PPARD]、SIRT1）的表达。
结论/解读：这些发现表明，BPD后体重减轻通过独立于参与线粒体生物发生/活性的基因表达的机制对胰岛素敏感性产生有益影响。此外，2型糖尿病患者体重减轻时基因表达未改变而NGT患者体重减轻时基因表达被诱导这一观察结果提示存在遗传因素。
