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

 描述(申请人提供)：胃旁路手术(GB)和袖状胃切除术后立即导致糖尿病缓解。GB治疗后血糖峰值提前、峰值降低，胰岛素和胃肠激素、胰岛素样肽1(GLP-1)和葡萄糖依赖胰岛素样肽(GIP)升高，对进食的反应。GB的非重量依赖性升糖作用归因于增加肠岛轴活动(胰岛素效应)和改变葡萄糖流量。虽然GB的升糖效应在一组患有毁灭性的高胰岛素血症低血糖综合征晚期并发症的受试者中被夸大，但与GB相比，SG后这些变化较小，提示胰岛功能的变化是连续的。人们已经认识到，GLP-1刺激的餐后胰岛素分泌在GB后更大，特别是在患有 GB相关低血糖。然而，GIP或肠岛轴的非激素成分(即营养和神经-主要是副交感神经系统[PNS]刺激)对GB后胰岛素分泌的影响完全未知，SG后肠岛轴活动的作用也是完全未知的。在GB受试者的低血糖期间，进食食物增加了胰岛素的分泌；但尚不清楚在这种情况下，进食诱导的ç细胞分泌是由于GLP-1的葡萄糖非依赖作用，还是由于PNS活性的增加，或者是直接的营养作用。我们的主要假设是，GB和SG的血糖改善作用是由于胰岛素(GLP-1和GIP)和三七总皂甙活性对胰岛素分泌的影响不同，而与常量营养素组成或血糖水平无关。我们还假设，在有GB后低血糖的受试者中，胰岛功能增强的肠岛活动比那些没有发生低血糖的受试者更强。为了验证我们的假设，我们将：1)确定GLP-1和GIP在GB或SG后胰岛素介导的胰岛细胞对葡萄糖和蛋白质摄取的反应中的作用。我们假设，在血糖和蛋白质挑战期间，与非手术对照组相比，GB后，尤其是低血糖患者和SG后，内源性GLP-1和GIP的餐后-细胞效应更大。2)测定餐后GLP-1和副交感神经活动对餐后低血糖钳夹下胰岛细胞功能的影响。我们假设，在这种情况下，肠胰岛活动的神经和激素方面(即PNS活动和GLP-1作用)对餐后？细胞输出的贡献在GB后的受试者中将比SG和非手术对照组的受试者更大。有GB相关性低血糖的患者，无症状的GB和SG个体，以及匹配的非手术对照组将被研究。为了确定GB通过改变葡萄糖通量介导的升糖效果，第五组非手术受试者将在目标1中模拟GB后的葡萄糖通量速率进行十二指肠内注射。本项目将仔细描述由于GB或SG而导致的长期重建的胃肠道对胰岛细胞功能的影响，以及如何将对肠岛轴活动的操纵用于治疗和预防目的。

 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.