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）：尽管尚未阐明鲁克斯en-y胃旁路糖尿病的糖尿病的机制，但食物从十二指肠的手术转移以及早期将营养物质递送到空肠的手术转移似乎都起着核心作用。葡萄糖抑制性多肽（GIP）是从近端小肠释放的肠降凝蛋白，并增强了葡萄糖含量中胰岛胰岛素的释放。我们假设GIP在Roux-en-Y胃旁路后的糖尿病解决中起着至关重要的作用。在特定的目标1中，我们假设在十二指肠和jejunal排除后慢性刺激养分将导致GIP水平降低，胰腺GIP受体的上调以及GIP受体在胰岛胰岛细胞中的胰岛素诱导的胰岛素分泌的回归。在糖尿病和非糖尿病大鼠中将进行改良的roux-en-y胃旁路。血浆GIP，胰岛素和葡萄糖水平将在手术后四周评估。四个星期后，这些动物将接受淋巴瘘手术，以评估胃肠道淋巴的GIP含量。淋巴水平将与血浆GIP水平进行比较。淋巴采样后，将收集胰岛细胞以用于GIP mRNA和蛋白质。此外，将培养胰岛以测试Duodenal-Jejunal排除后GIP的肠降凝素功能是否恢复。在特定的目标2中，我们假设非糖尿病大鼠的慢性GIP输注将通过下调GIP受体表达并使GIP诱导的胰岛素分泌的信号传导降低，从而导致葡萄糖稳态恶化。同样，我们预计糖尿病大鼠RYGB后的慢性GIP输注将抑制II型DM的分辨率，从而强调GIP GIP受体相互作用对RYGB后糖尿病的分辨率的重要性。 GIP将通过腹膜内植入的泵长期注入四个星期，将评估GIP输注对血浆胰岛素和葡萄糖的影响。该模型将在胃旁路之前和之后用于糖尿病和非糖尿病大鼠。经过四周的GIP处理后，将收集胰岛细胞并分离以进行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：糖尿病是美国的第六大死亡原因，有60％的II型糖尿病患者肥胖。在roux-en-y-y胃旁路后，有90％的II型糖尿病患者完全解决了糖尿病，这是一种手术手术，用于病态肥胖的体重减轻。确定该分辨率的机制不仅提供了新药物疗法的可能性，而且还提供了新型手术作为II型糖尿病的潜在治疗方法。