The weight-independent effects of bariatric surgeries on islet cell function

减肥手术对胰岛细胞功能的与体重无关的影响

• 批准号: 9210867
• 负责人: Marzieh Salehi
• 金额: $ 51.39万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210867
• 关键词: weight; independent; effects; bariatric; surgeries

 DESCRIPTION (provided by applicant): Gastric bypass surgery (GB) and sleeve gastrectomy induce diabetes remission immediately after surgery. Patients after GB have earlier and higher peak, and lower nadir, glucose levels along with larger insulin and gut hormone, glucagon like-peptide 1 (GLP-1) and glucose dependent insulinotropic peptide (GIP), response to meal ingestion. The weight-independent glycemic effect of GB has been attributed to increase in enteroinsular- axis activity (incretin effect) and altered glucose flux. While the glycemic effectsof GB is exaggerated in a subset of subjects with a devastating late-complication of hyperinsulinemia hypoglycemia syndrome, these changes are smaller after SG compared to GB, suggestive of a continuum in alteration in islet function. It has been recognized that GLP-1-stimulated postprandial insulin secretion is larger after GB, and especially so in individuals with the GB-related hypoglycemia. However, the effects of GIP or non-hormonal components of the enteroinsular axis (i.e., nutrient and neural -mainly parasympathetic nervous system [PNS]- stimulation) on insulin secretion after GB are completely unknown, as is the role of enteroinsular axis activity after SG. Meal ingestion increases insulin secretion during hypoglycemia in GB subjects; but it is unknown whether meal- induced ß-cell secretion in this setting is due the glucose-independent actions of GLP-1, or to increased PNS activity, or direct nutrient effect. Our main hypothesis is that the improved glycemic effects of GB and SG are due to variation in the effect of incretins (GLP-1 and GIP) and PNS activity on insulin secretion independent of macronutrient composition or glycemic levels. We also hypothesize that enhanced enteroinsular activity on islet function are greater in subjects with post-GB hypoglycemia than in those without. To test our hypothesis we will: 1) Identify the contribution of GLP-1 and GIP to the incretin-mediated islet cell response to glucose and protein ingestion after GB or SG. We hypothesize that postprandial ß-cell effects of endogenous GLP-1 and GIP are larger after GB, especially in those with hypoglycemia, and after SG compared to the non-surgical controls during both glucose and protein challenges. 2) Determine the contribution of GLP-1 and parasympathetic activity to islet cell function during hypoglycemic clamp after meal ingestion in individuals after GB or SG. We hypothesize that the contribution of neural and hormonal aspects of enteroinsular activity (i.e., PNS activity and GLP-1 action) to postprandial ß-cell output in this setting will be larger in subjects after GB compared to those after SG and non-surgical controls. Patients with GB-related hypoglycemia, asymptomatic GB and SG individuals, and matched non-operated controls will be studied. To determine the glycemic effects of GB mediated by altered glucose flux, a fifth group of non-operated subjects will receive glucose intraduodenally simulating the rate of glucose flux after GB in Aim 1. This project will carefully characterize the effects of a long-lasting restructured GI tract as a result of GB or SG on islet cell function, and how manipulation of enteroinsular-axis activity can be utilized for therapeutic and preventive purposes.

 描述（由适用提供）：胃旁路手术（GB）和袖胃切除术在手术后立即诱导糖尿病。 GB后的患者具有较早和较高的峰值，较低的Nadir，葡萄糖水平以及较大的胰岛素和肠hors，胰高血糖素类似肽1（GLP-1）以及依赖性葡萄糖胰岛素肽（GIP），对摄入饮食的反应。 GB的重量非依赖性血糖效应已归因于肠轴活性的增加（降直型蛋白效应）和葡萄糖通量改变。虽然GB的血糖效应被夸大了在高胰岛素血症综合症的毁灭性晚期复杂的一部分中，但与GB相比，SG后这些变化较小，暗示了胰岛功能的变化。人们已经认识到，GB后GLP-1刺激的餐后胰岛素分泌更大，尤其是在患有 与GB相关的低血糖。然而，肠道轴的GIP或非激素成分（即营养和神经 - 副交感神经神经系统[PNS] - 刺激）对GB后胰岛素分泌的影响是完全未知的，SG后肠轴活动的作用也是如此。摄入量增加了GB受试者低血糖期间胰岛素分泌的增加；但是尚不清楚在这种情况下，在这种情况下，粉诱导的ß细胞分泌是由于GLP-1的葡萄糖独立作用，增加PNS活性还是直接营养效应。我们的主要假设是，GB和SG的血糖作用的改善是由于增加蛋白（GLP-1和GIP）的作用变化，PNS活性对胰岛素分泌对胰岛素分泌的作用无关，而与大量营养素组成或血糖水平无关。我们还假设，在具有GB后GB后假设的受试者中，对胰岛功能的增强的肠内活性更大：1）确定GLP-1和GIP对GB或SG后添加介导的胰岛细胞对葡萄糖和蛋白质摄取的介导的胰岛细胞反应的贡献。我们假设内源性GLP-1和GIP的餐后ß细胞作用在GB后，尤其是在低血糖的患者之后，与葡萄糖和蛋白质挑战期间的非手术对照相比，SG之后的SG后SG较大。 2）确定在GB或SG后摄入饮食后降血糖夹期间GLP-1和副交感神经对胰岛细胞功能的贡献。我们假设，与SG和非外科对照组相比，GB后的受试者中，在这种情况下，在这种情况下，在这种情况下，在这种情况下，在这种情况下，在这种情况下，在这种情况下，肠内活性（即PNS活性和GLP-1动作）的神经和马的方面的贡献将更大。患有与GB相关的低血糖，不对称GB和SG患者以及匹配的非手术对照的患者将进行研究。 To determine the glycemic effects of GB mediated by altered glucose flux, a fifth group of non-operated subjects will receive glucose intraduodendally simulating the rate of glucose flux after GB in Aim 1. This project will carefully characterize the effects of a long-lasting restored GI tract as a result of GB or SG on islet cell function, and how manipulation of enteroinsular-axis activity can be utilized for治疗和预防目的。