WEIGHT LOSS-INDEPENDENT METABOLIC EFFECTS OF ROUX-EN-Y GASTRIC BYPASS IN DIABETES

Roux-en-Y 胃绕道术对糖尿病患者的与减肥无关的代谢效应

• 批准号: 9117508
• 负责人: Samuel Klein
• 金额: $ 52.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117508
• 关键词: Acute; Address; Behavior Therapy; Body Weight decreased; Body mass index; Bolus Infusion; Bypass; Cell physiology; Complication; Control Groups; Development; Diabetes Mellitus; Diet; Diet therapy; Disease remission; Dose; Energy Intake; Fatty Acids; Functional disorder; Gastric Bypass; Glucose; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Health; Hepatic; Homeostasis; Hormones; In complete remission; Infusion procedures; Ingestion; Insulin; Insulin Resistance; Intravenous; Kinetics; Label; Lead; Liver; Measurable; Measures; Mechanics; Medical; Metabolic; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Octreotide; Operative Surgical Procedures; Oral; Organ; Outcome Measure; Pancreas; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Physiological; Plasma; Procedures; Rodent Model; Route; Skeletal Muscle; Staging; Stomach; Study Subject; Testing; Therapeutic Effect; Tracer; Upper digestive tract structure; Weight; bariatric surgery; blood glucose regulation; fatty acid metabolism; feeding; global health; glucagon-like peptide 1; glucose disposal; glucose production; glycemic control; improved; indexing; insulin secretion; insulin sensitivity; non-diabetic; response; somatostatin analog

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a major complication of obesity, and is caused by multi-organ insulin resistance in conjunction with inadequate pancreatic insulin secretion. Weight loss in obese people who have T2D can improve both insulin secretion and insulin action, and even result in complete remission (normal glycemic control without diabetes medications). Bariatric surgery causes marked weight loss and is the most effective available therapy for T2D. Moreover, it has been proposed that surgical procedures that bypass the upper gastrointestinal tract, such as roux-en-Y gastric bypass (RYGB), have weight loss-independent effects in achieving glycemic control. Although it is clear that RYGB surgery has profound effects on the metabolic response to oral glucose or meal ingestion, it is still not known whether RYGB has long-term, clinically important, weight loss-independent effects on the key factors responsible for diabetes remission in patients with T2D, namely �-cell function, insulin sensitivity, and integrated 24-h glucose and fatty acid homeostasis, after marked weight loss has been achieved. Therefore, the overall goal of this proposal is to carefully address these issues in obese subjects with T2D. Accordingly, we will evaluate the effects of 16%-18% weight loss induced by either RYGB surgery or a low-calorie diet (LCD), matched for energy intake and rate of weight loss, on: 1) hepatic and skeletal muscle insulin sensitivity (assessed by using the hyperinsulinemic-euglycemic pancreatic clamp procedure, and by evaluating the suppression of endogenous glucose production in response to mixed meal ingestion), 2) �-cell function (i.e. insulin secretion and disposition index; assessed i response to both an oral mixed meal and an intravenous glucose bolus), and 3) 24-h glucose and free fatty acid (FFA) homeostasis (assessed by measuring glucose and FFA concentrations and kinetics over 24 h) in obese (body mass index 35-55 kg/m2) subjects with T2D. In addition, we will study subjects with T2D who are likely to have a measurable beneficial response to weight loss therapy (i.e. those with duration of T2D <10 yrs, who have reasonable glycemic control, and who are not being treated with insulin) to increase our ability to detect a potential difference between surgery and diet therapies. We hypothesize that, compared with the same weight loss induced by LCD therapy, RYGB will lead to: i) greater improvement in hepatic but not skeletal muscle insulin sensitivity; ii) greater improvement in �-cell function assessed in response to ingested glucose but not intravenous glucose; and iii) greater improvement in 24-h glucose and FFA metabolism. This project will answer the question of whether RYGB has clinically important weight loss-independent effects on the metabolic processes that regulate glycemic control after patients with T2D have lost a considerable amount of weight. The results from this study are of physiological and medical importance, and will help identify specific metabolic targets for future research studies.

描述（由适用提供）：2型糖尿病（T2D）是肥胖的主要并发症，是由多器官胰岛素耐药性引起的，胰腺胰岛素分泌不足。患有T2D的肥胖者的体重减轻可以改善胰岛素分泌和胰岛素作用，甚至可以完全缓解（没有糖尿病药物的正常血糖控制）。减肥手术会导致体重减轻，是T2D最有效的治疗方法。此外，已经提出，绕过胃肠道上部的外科手术，例如roux-en-y胃旁路（RYGB），在达到血糖控制方面具有重量损失的影响。尽管很明显，RYGB手术对对口腔葡萄糖或摄入的代谢反应具有深远的影响，但尚不清楚RYGB是否具有长期，临床重要的，减肥无关的影响，对负责T2D患者的糖尿病缓解的关键因素，并在T2D患者中的糖尿病缓解，并在胰岛素功能，胰岛素敏感性和富度敏感性，胰岛素较高的效果，及其酸度较高，并富含胰岛素敏感性，促进了HONDES，并富于HONDES，并且是富含胰岛素的敏感性，并且富含毒性敏感性，并且是富含胰岛素敏感性的，并且富于HONDES，并且是酸性的，并且是胰岛素较高的效果。成就了。因此，该提案的总体目标是仔细解决T2D肥胖受试者中的这些问题。据此，我们将评估RYGB手术或低热量饮食（LCD）诱导的16％-18％的体重减轻的影响，以匹配能量摄入量和体重减轻速率，ON：1）肝肌肉和骨骼肌胰岛素敏感性（通过使用高胰岛素 - euguglecymecture pancormity pancenture pangeriatient pangeriatient spendure pangeriation spendure pangentic pangeriation spenduce pangentic pangentic pangentip pangentic pangentip， in response to mixed meal ingestion), 2) �-cell function (i.e. insulin secretion and disposition index; assessed i response to both an oral mixed meal and an intravenous glucose bolus), and 3) 24-h glucose and free fatty acid (FFA) homeostasis (assessed by measuring glucose and FFA concentrations and kinetics over 24 h) in obese (body mass index 35-55 kg/m2）具有T2D的受试者。此外，我们将研究具有T2D的受试者，他们可能对减肥疗法具有可衡量的有益反应（即T2D持续时间<10岁的人，具有合理的血糖控制，并且未接受胰岛素治疗的人可以提高我们在手术和饮食治疗之间检测潜在差异的能力。我们假设，与LCD疗法引起的相同体重减轻相比，RYGB将导致：i）肝肌肉胰岛素敏感性的改善； ii）根据摄入的葡萄糖而不是静脉内葡萄糖评估的细胞功能的更大改善； iii）24小时葡萄糖和FFA代谢的改善。该项目将回答一个问题，即RYGB是否对在T2D患者失去考虑的体重量失去的代谢过程中是否对调节血糖控制的代谢过程具有临床重要的减肥作用。这项研究的结果具有物理和医学的重要性，将有助于确定未来研究的特定代谢靶标。