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: 9102074
• 负责人: Marzieh Salehi
• 金额: $ 69.24万
• 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 2017-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102074
• 关键词: Affect; Atropine; Beta Cell; Body Weight decreased; Cell physiology; Cell secretion; Cells; Complication; Dependency; Development; Diabetes Mellitus; Diet; Diet Modification; Disease remission; Gastrectomy; Gastric Inhibitory Polypeptide; Gastrointestinal tract structure; Glucagon; Glucose; Goals; Hormonal; Hormones; Human; Hyperinsulinism; Hypoglycemia; Individual; Ingestion; Insulin; Islet Cell; Lead; Macronutrients Nutrition; Mediating; Medical; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Operative Surgical Procedures; Output; Parasympathetic Nervous System; Patients; Phenotype; Physiological; Preventive; Procedures; Proteins; Reactive hypoglycemia; Recurrence; Regulation; Role; Signal Transduction; Stimulus; Subgroup; Syndrome; Testing; Therapeutic; Variant; Weight; bariatric surgery; blood glucose regulation; diabetic; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; improved; insulin secretion; islet; protein B; public health relevance; relating to nervous system; response; visceral afferent nerve

 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（由申请人提供）：胃绕道手术（GB）和袖状胃切除术在手术后立即导致糖尿病缓解，GB后患者的血糖水平出现更早、更高的峰值和更低的最低点，同时胰岛素和肠道激素、胰高血糖素样肽也更大。 1 (GLP-1) 和葡萄糖依赖性促胰岛素肽 (GIP)，对膳食摄入的反应 GB 的与体重无关的血糖效应归因于肠岛轴活性的增加。 （肠促胰素效应）和改变的葡萄糖通量虽然在患有高胰岛素血症低血糖综合征的破坏性晚期并发症的受试者中夸大了 GB 的血糖效应，但与 GB 相比，SG 后的这些变化较小，表明胰岛的变化是连续的。人们已经认识到，GB 后 GLP-1 刺激的餐后胰岛素分泌量更大，尤其是在患有 GB 的个体中。 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是完全未知的。 SG 后肠岛轴活动会增加 GB 受试者低血糖期间的胰岛素分泌，但尚不清楚是否由膳食引起。在这种情况下，β-细胞分泌是由于 GLP-1 的葡萄糖独立作用，或 PNS 活性增加，或直接营养作用。我们的主要假设是 GB 和 SG 改善的血糖效应是由于 GLP-1 的变化。肠促胰素（GLP-1 和 GIP）和三七总皂甙活性对胰岛素分泌的影响与常量营养素成分或血糖水平无关，我们还发现，GB 后受试者的肠岛活性对胰岛功能的增强更大。为了检验我们的假设，我们将： 1) 确定 GLP-1 和 GIP 对 GB 或 SG 后肠促胰岛素介导的胰岛细胞对葡萄糖和蛋白质摄入的反应的贡献。在葡萄糖和蛋白质挑战期间，与非手术对照相比，GB 后（尤其是低血糖患者）和 SG 后内源性 GLP-1 和 GIP 的含量更大。 2) 确定 GB 或 SG 后个体餐后低血糖钳夹过程中 GLP-1 和副交感神经活性对胰岛细胞功能的贡献。与 SG 和非手术对照相比，GB 后的受试者在这种情况下餐后 β 细胞输出量（1 个动作）会更大。将研究与 GB 相关的低血糖、无症状 GB 和 SG 个体以及匹配的未手术对照，以确定由改变的葡萄糖通量介导的 GB 的血糖影响，第五组非手术受试者将接受模拟速率的十二指肠内葡萄糖。目标 1 中 GB 后葡萄糖通量的变化。该项目将仔细描述 GB 或 SG 导致的长期胃肠道重组对胰岛细胞功能的影响，以及如何利用肠岛轴活动的操纵来达到治疗和预防目的。