Mechanisms of Diabetes Control After Weight Loss Surgery

描述(申请人提供)：肥胖和2型糖尿病(DM)在美国呈上升趋势。寻求减肥手术的患者中有三分之一患有糖尿病。虽然所有的手术都能显著减轻体重，并且常常“治愈”糖尿病，但胃旁路手术(GBP)对糖尿病的快速起效和益处的大小到目前为止一直让临床科学家感到困惑。有限的数据表明，GBP后糖尿病的改善非常迅速，可能不完全是体重减轻的原因。糖尿病患者胰岛素分泌受损，而GBP术后则有所改善，可能是由于手术后特殊的解剖结构变化。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有改善，但GBP后胰岛素效应的改善可能是这种手术特有的。我们将在AIM 1中确定GBP后胰岛素分泌的胰岛素效应是否比同等饮食诱导的减肥后更大。我们将比较随机分为极低卡路里饮食组或GBP组的肥胖糖尿病患者，3至6周的等量体重减轻对胰岛素效应的影响(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，绕过上肠道，而不是减轻体重本身，可以改善GBP后糖尿病患者的糖耐量。目标2将确定GBP后的胰岛素效应是否比胃束带(一种未知的改变胰岛素的程序)更大。我们将在GBP或胃束带术前和9个月后测量胰岛素的效果。糖尿病患者胰岛素分泌受损的一个主要决定因素是胰岛素敏感性(SI)降低。饮食诱导的减肥同样改善了胰岛素的分泌和硅。在GBP后，胰岛素分泌的相对变化和SI之间的解离已被报道，这表明除了补偿SI的变化之外，胰岛素的分泌可能涉及另一种机制。目的3确定GBP术后胰岛素分泌(AIR G)相对于Si的变化是否大于胃束带术后。我们将在手术前和术后9个月用静脉葡萄糖耐量试验来测量，对于同等的Si变化，GBP术后的airG是否比胃束带术后改善得更多。随着越来越多的肥胖糖尿病患者接受GBP，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.