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

GIP 是否参与 Roux-en-y 胃绕道手术后糖尿病的缓解？

• 批准号: 7545584
• 负责人: Tammy Lyn Kindel
• 金额: $ 5.85万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545584
• 关键词: Animal Model; Animals; Bariatrics; Binding; Blood Circulation; Blood Glucose; Body Weight decreased; Bypass; Cause of Death; Chronic; Condition; Defect; Deterioration; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Down-Regulation; Duodenum; Endopeptidases; Evaluation; Excision; Exclusion; Fistula; Food; Functional disorder; Gastric Bypass; Glucose; Harvest; Human; Hyperglycemia; Implant; Individual; Infusion Pumps; Infusion procedures; Insulin; Intestines; Islet Cell; Islets of Langerhans; Killer Cells; Laboratories; Lymph; Lymphatic; Macronutrients Nutrition; Messenger RNA; Methods; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Pancreas; Patients; Peptide Hydrolases; Personal Satisfaction; Pharmacotherapy; Plasma; Play; Procedures; Proteins; Public Health; Pump; Rate; Resolution; Role; Sampling; Serum; Signal Transduction; Small Intestines; Structure of beta Cell of islet; Testing; Transcriptional Activation; Up-Regulation; Week; attenuation; bariatric surgery; blood glucose regulation; concept; diabetic; diabetic rat; gastric inhibitory polypeptide receptor; gastrointestinal; insulin secretion; intraperitoneal; intraperitoneal infusion; islet; jejunum; non-diabetic; novel; polypeptide; protein expression; receptor; receptor expression; response; restoration

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.

描述（由申请人提供）：尽管 roux-en-y 胃绕道手术后解决糖尿病的机制尚未阐明，但通过手术将食物从十二指肠转移到空肠并尽早将营养物质输送到空肠似乎发挥了核心作用。角色。葡萄糖抑制多肽（GIP）是一种从小肠近端释放的肠促胰岛素，在葡萄糖存在的情况下增强胰腺释放胰岛素。我们假设 GIP 在 roux-en-y 胃绕道手术后糖尿病的缓解中发挥着关键作用。在具体目标 1 中，我们假设十二指肠空肠排斥后去除营养物的慢性刺激将导致 GIP 水平下降、胰腺 GIP 受体上调以及 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 胃绕道手术。手术后 4 周内将评估血浆 GIP、胰岛素和葡萄糖水平。四周后，动物将接受淋巴瘘手术，以评估胃肠淋巴中是否存在 GIP。将淋巴液水平与血浆 GIP 水平进行比较。淋巴取样后，将收集胰岛细胞以获取 GIP mRNA 和蛋白质。此外，将培养胰岛以测试十二指肠空肠排斥后GIP的肠促胰素功能是否已恢复。在具体目标 2 中，我们假设非糖尿病大鼠的长期 GIP 输注将通过下调 GIP 受体表达并减弱 GIP 诱导的胰岛素分泌信号而导致葡萄糖稳态恶化。此外，我们预计糖尿病大鼠 RYGB 后慢性 GIP 输注将抑制 II 型 DM 的消退，这凸显了 GIP-GIP 受体相互作用对 RYGB 后糖尿病消退机制的重要性。 GIP将通过腹腔内植入泵长期输注4周，并评估GIP输注对血浆胰岛素和血糖的影响。该模型将用于胃绕道手术前后的糖尿病和非糖尿病大鼠。 GIP 治疗 4 周后，将收获并分离胰岛细胞，以检测 GIP mRNA 和蛋白表达以及 GIP 刺激胰岛细胞胰岛素分泌的效果。公共健康相关性：糖尿病是美国第六大死因，60% 的 II 型糖尿病患者患有肥胖症。 90% 的 II 型糖尿病患者在接受 Roux-en-y 胃绕道手术（一种针对病态肥胖者进行减肥的外科手术）后，糖尿病得到完全缓解。确定这一解决方案的机制不仅为新药物治疗提供了可能性，而且还为手术作为 II 型糖尿病的潜在治疗方法提供了新用途。