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: 8864610
• 负责人: Marzieh Salehi
• 金额: $ 8.89万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8864610
• 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; Relative (related person); 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）：胃旁路手术（GB）和袖状胃切除术可在术后立即诱导糖尿病缓解。GB后的患者血糖水平峰值更早、更高，最低点更低，同时胰岛素和肠道激素、胰高血糖素样肽1（GLP-1）和葡萄糖依赖性促胰岛素肽（GIP）对膳食摄入的反应更大，沿着。GB的体重非依赖性血糖效应归因于肠胰岛素轴活性增加（肠促胰岛素效应）和葡萄糖通量改变。虽然GB的血糖效应在一个具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亚组中被夸大，但与GB相比，SG后这些变化较小，提示胰岛功能的连续改变。已经认识到，GLP-1刺激的餐后胰岛素分泌在GB后更大，尤其是在患有以下疾病的个体中更大。 与GB相关的低血糖然而，GIP或肠胰岛轴的非激素成分（即，营养素和神经-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后肠胰岛轴活动的作用也是如此。进食增加GB受试者低血糖期间的胰岛素分泌;但尚不清楚这种情况下进餐诱导的胰岛β细胞分泌是否是由于GLP-1的葡萄糖非依赖性作用，或PNS活性增加，或直接营养作用。我们的主要假设是，GB和SG的改善血糖效应是由于肠促胰岛素（GLP-1和GIP）和PNS活性对胰岛素分泌的影响的变化，而与大量营养素组成或血糖水平无关。我们还假设，增强的肠胰岛活动对胰岛功能更大的受试者后GB低血糖比那些没有。为了验证我们的假设，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。我们假设，与葡萄糖和蛋白质挑战期间的非手术对照相比，GB后（尤其是低血糖患者）和SG后内源性GLP-1和GIP的餐后β细胞效应更大。2)确定GB或SG后进食后低血糖钳夹期间GLP-1和副交感神经活性对胰岛细胞功能的贡献。我们假设肠岛活动的神经和激素方面的贡献（即，与SG和非手术对照组相比，GB后受试者在这种情况下的PNS活性和GLP-1作用）与餐后胰岛β细胞输出的比值将更大。将研究患有GB相关低血糖的患者、无症状GB和SG个体以及匹配的非手术对照。为了确定由改变的葡萄糖流量介导的GB的血糖效应，第五组非手术受试者将在尿道内接受葡萄糖，模拟目标1中GB后的葡萄糖流量速率。该项目将仔细表征GB或SG对胰岛细胞功能的长期重建胃肠道的影响，以及如何操纵肠胰岛素轴活动可用于治疗和预防目的。