Is GIP Involved in the Resolution of Diabetes After Roux-en-y Gastric Bypass?

描述（由申请人提供）：尽管Roux-en-y胃旁路术后糖尿病消退的机制尚未阐明，但通过手术将食物从十二指肠转移并将营养物质早期输送至空肠似乎起着核心作用。葡萄糖抑制多肽（Glucose-inhibitory polypeptide，GIP）是近端小肠分泌的一种肠促胰岛素，在葡萄糖存在下可促进胰腺释放胰岛素。我们假设GIP在Roux-en-Y胃旁路术后糖尿病的解决中起着关键作用。在具体目标1中，我们假设在空肠-空肠阻断后去除营养物的慢性刺激将导致GIP水平降低、胰腺GIP受体上调和GIP受体诱导的胰岛细胞胰岛素分泌恢复。将在糖尿病和非糖尿病大鼠中进行改良的roux-en-y胃旁路术。将在术后4周评估血浆GIP、胰岛素和葡萄糖水平。四周后，动物将接受淋巴瘘手术，以评价胃肠道淋巴是否存在GIP。将淋巴水平与血浆GIP水平进行比较。淋巴取样后，收获胰岛细胞用于GIP mRNA和蛋白质。此外，将培养胰岛以测试在回肠-空肠阻断后GIP的肠促胰岛素功能是否已经恢复。在具体目标2中，我们假设在非糖尿病大鼠中慢性GIP输注将通过下调GIP受体表达和减弱GIP诱导的胰岛素分泌的信号传导而导致葡萄糖稳态的恶化。此外，我们预期糖尿病大鼠RYGB后的慢性GIP输注将抑制II型DM的消退，突出了GIP-GIP受体相互作用对RYGB后糖尿病消退机制的重要性。将通过腹膜内植入泵长期输注GIP 4周，并评价GIP输注对血浆胰岛素和葡萄糖的影响。该模型将在胃旁路手术前后用于糖尿病和非糖尿病大鼠。在GIP处理四周后，收获并分离胰岛细胞用于GIP mRNA和蛋白质表达以及GIP刺激胰岛细胞胰岛素分泌的作用。公共卫生相关性：糖尿病是美国第六大死亡原因，60%的II型糖尿病患者肥胖。90%的II型糖尿病患者在Roux-en-y胃旁路手术后糖尿病完全消退，Roux-en-y胃旁路手术是一种为病态肥胖患者减肥而进行的外科手术。确定这种解决机制不仅提供了新的药物治疗的可能性，而且还提供了手术作为II型糖尿病潜在治疗方法的新用途。

DESCRIPTION (provided by applicant): Although the mechanism to the resolution of diabetes after roux-en-y gastric bypass has yet to be elucidated, the surgical diversion of food from the duodenum with early delivery of nutrients to the jejunum appears to play a central role. Glucose-inhibitory polypeptide (GIP) is an incretin released from the proximal small intestine and enhances the release of insulin from the pancreas in the presense of glucose. We hypothesize that GIP plays a critical role in the resolution of diabetes after roux-en-y gastric bypass. In Specific Aim 1, we hypothesize that removal of chronic stimulation of nutrients after duodenal-jejunal exclusion will result in decreased levels of GIP, an up-regulation of pancreatic GIP receptors and a return of GIP receptor induced insulin secretion in pancreatic islet cells. A modified roux-en-y gastric bypass will be performed in both diabetic and non-diabetic rats. Plasma GIP, insulin, and glucose levels will be assessed for four weeks after surgery. After four weeks, the animals will undergo a lymphatic fistula procedure for evaluation of gastrointestinal lymph for the presense of GIP. The lymph levels will be compared to plasma GIP levels. Following lymphatic sampling, pancreatic islet cells will be harvested for GIP mRNA and protein. Further, islets will be cultured to test if the incretin function of GIP has been restored after duodenal-jejunal exclusion. In Specific Aim 2, we hypothesize that chronic GIP infusion in non-diabetic rats will result in the deterioration of glucose homeostasis by down-regulation of GIP receptor expression and blunting the signaling of GIP induced insulin secretion. Also, we expect that chronic GIP infusion after RYGB in diabetic rats will inhibit the resolution of Type II DM, highlighting the importance of GIP-GIP receptor interaction to the mechanism of resolution of diabetes after RYGB. GIP will be chronically infused via an intraperitoneal implanted pump for four weeks, and the effect of GIP infusion on plasma insulin and glucose will be evaluated. This model will be used in both diabetic and non-diabetic rats before and after gastric bypass. After the four weeks of GIP treatment, the pancreatic islet cells will be harvested and isolated for GIP mRNA and protein expression as well as the effect of GIP stimulation of pancreatic islet cell insulin secretion. PUBLIC HEALTH RELEVANCE: Diabetes is the sixth leading cause of death in the US and 60% of individuals with type II diabetes mellitus are obese. 90% of patients with type II diabetes mellitus have complete resolution of diabetes after roux-en-y gastric bypass, a surgical procedure performed for weight loss in the morbidly obese. Identifying the mechanism for this resolution offers not only the possibility for new drug therapy but also the novel use of surgery as a potential cure for type II diabetes mellitus.