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。寻求减肥手术的患者中有三分之一患有糖尿病。尽管所有手术都能显著减轻体重，并经常“治愈”糖尿病，但胃分流术（GBP）对糖尿病的快速起效和巨大益处迄今令临床科学家感到困惑。有限的数据表明，GBP后DM的改善非常迅速，可能不能完全由体重减轻来解释。肠促胰岛素（进食后分泌的肠道肽，可增强胰岛素分泌）的分泌在糖尿病患者中受损，在GBP后改善，可能是由于手术后特定的解剖改变。虽然一些胰岛素分泌受损的决定因素，如糖毒性，在饮食或手术减肥后同样得到改善，但GBP后肠促胰岛素效果的改善可能是该手术所特有的。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是否比同等饮食诱导的减肥后更大。我们将比较肥胖糖尿病患者随机分配到极低热量饮食或GBP， 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）葡萄糖负荷后胰岛素分泌的差异）。实验数据表明，旁路上肠，而不是减肥本身，可以改善GBP后DM患者的葡萄糖耐量。AIM 2将确定GBP后肠促胰岛素效应的大小是否大于胃束带（一种未知的手术会改变肠促胰岛素）。我们将在GBP或胃束带治疗前和治疗后9个月测量肠促胰岛素的效果。糖尿病患者胰岛素分泌受损的主要决定因素是胰岛素敏感性降低（Si）。饮食引起的体重减轻对胰岛素分泌和Si均有促进作用。在GBP后，胰岛素分泌的相对变化与Si之间的解离已被报道，提示除了补偿Si的变化外，可能还有一种机制参与胰岛素分泌。AIM 3将确定GBP后胰岛素分泌（AIRg）相对于Si的变化是否比胃束带后更大。我们将在手术前和手术后9个月通过静脉葡萄糖耐量试验来测量，对于Si的等效变化，GBP术后AIRg是否比胃束带术后改善更多。随着越来越多的肥胖糖尿病患者接受GBP治疗，了解糖尿病改善的机制变得越来越重要。

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.