Mechanisms of Diabetes Control After Weight Loss Surgery

描述（由申请人提供）：肥胖和2型糖尿病（DM）在美国正在增加。三分之一寻求减肥手术的患者患有糖尿病。尽管所有手术都能显著减轻体重，并经常“治愈”DM，但胃旁路术（GBP）对DM的快速发作和益处的大小迄今为止一直困扰着临床科学家。有限的数据表明，GBP后DM的改善发生得非常迅速，并且可能不完全是体重减轻造成的。肠促胰岛素分泌（响应于增加胰岛素分泌的膳食而分泌的肠肽）在DM中受损，并且在GBP后改善，这可能是由于该手术后的特定解剖学变化。虽然胰岛素分泌受损的一些决定因素，如葡萄糖毒性，在饮食或手术减肥后同样得到改善，但GBP后肠促胰岛素效应的改善可能是该手术特有的。我们将在AIM 1中确定GBP后肠促胰岛素对胰岛素分泌的影响程度是否大于同等饮食诱导的体重减轻后。我们将在随机分配至极低热量饮食或GBP的肥胖糖尿病患者中比较3至6周等效体重减轻对肠促胰岛素效应的影响（口服和静脉（IV）葡萄糖负荷相当后胰岛素分泌的差异）。实验数据表明，绕过上消化道，而不是体重减轻本身，提高GBP后DM的葡萄糖耐量。目的2是确定GBP后肠促胰岛素效应的程度是否大于胃束带术（一种未知的改变肠促胰岛素的手术）。我们将在GBP或胃束带术前和术后9个月内测量肠促胰岛素的作用。DM中胰岛素分泌受损的主要决定因素是胰岛素敏感性（Si）降低。饮食引起的体重减轻同样改善胰岛素分泌和Si。在GBP之后，已经报道了胰岛素分泌的相对变化与Si之间的解离，这表明除了补偿Si变化之外的机制可能参与胰岛素分泌。目的3是确定GBP后胰岛素分泌（AIRg）的变化是否比胃束带后更大，相对于Si的变化。我们将在手术前和手术后9个月内通过IV葡萄糖耐量试验测量，对于Si的等效变化，GBP后AIRg的改善是否比胃束带术后更大。随着越来越多的肥胖糖尿病患者接受GBP，了解改善糖尿病的机制越来越重要。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (DM) are increasing in the US. One third of patients seeking bariatric surgery have DM. Although all surgeries result in significant weight loss and often 'cure' the DM, the rapid onset and the magnitude of the benefits of gastric bypass (GBP) on DM has thus far baffled clinical scientists. Limited data suggest that the improvement in DM after GBP occurs very rapidly, and may not be wholly accounted for by weight loss. Secretion of incretins (gut peptides secreted in response to meals which enhance insulin secretion) is impaired in DM and improves after GBP, possibly due to the specific anatomical changes after this surgery. While some determinants of impaired insulin secretion, such as glucotoxicity, improve equally after diet or surgical weight loss, the improvement in the incretin effect after GBP might be specific to this surgery. We will determine in AIM 1 whether the magnitude of the incretin effect on insulin secretion is greater after GBP than after an equivalent diet-induced weight loss. We will compare, in obese diabetic patients randomized to very low calorie diet or to GBP, the effect of a 3 to 6-week equivalent weight loss on the incretin effect (difference in insulin secretion after comparable oral and intravenous (IV) glucose loads). Experimental data suggest that bypassing the upper gut, rather than weight loss per se, improves glucose tolerance in DM after GBP. AIM 2 will be to determine whether the magnitude of the incretin effect is greater after GBP than after gastric banding (a procedure not known to change the incretins). We will measure the incretin effect before and up to 9 months after GBP or gastric banding. A major determinant of impaired insulin secretion in DM is decreased insulin sensitivity (Si). Diet-induced weight loss improves insulin secretion and Si equally. After GBP, dissociation between the relative changes in insulin secretion and Si has been reported, suggesting a mechanism other than compensation for changes in Si may be involved in insulin secretion. AIM 3 will be to determine whether the changes of insulin secretion (AIRg), relative to changes of Si, are greater after GBP than after gastric banding. We will measure, with IV glucose tolerance tests, before and up to 9 months after surgery, whether, for an equivalent change of Si, AIRg will improve more after GBP than after gastric banding. As more obese diabetic patients undergo GBP, understanding the mechanisms that produce improvement in their diabetes is increasingly important.