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（申请人提供）：2 型糖尿病 (T2D) 是肥胖的主要并发症，由多器官胰岛素抵抗和胰腺胰岛素分泌不足引起，患有 T2D 的肥胖者减轻体重可以改善胰岛素分泌。胰岛素作用，甚至导致完全缓解（无需糖尿病药物的正常血糖控制）可导致体重显着减轻，并且是治疗 T2D 最有效的疗法。绕过上胃肠道的手术，例如 roux-en-Y 胃绕道术 (RYGB)，在实现血糖控制方面具有与减肥无关的效果，尽管很明显 RYGB 手术对口服葡萄糖或膳食的代谢反应具有深远的影响。摄入后，目前尚不清楚 RYGB 是否对 T2D 患者糖尿病缓解的关键因素（即 β 细胞功能、胰岛素敏感性和血糖）具有长期、临床上重要的、与体重减轻无关的影响。因此，该提案的总体目标是仔细解决患有 T2D 的肥胖受试者的这些问题。因此，我们将评估 16%-18 的效果。 RYGB 手术或低热量饮食 (LCD) 引起的体重减轻百分比，与能量摄入和体重减轻率相匹配，涉及：1) 肝脏和骨骼肌胰岛素敏感性（通过使用高胰岛素-正常血糖胰钳夹手术，并通过评估混合膳食摄入对内源性葡萄糖产生的抑制），2）β-细胞功能（即胰岛素分泌和处置指数；评估对口服混合膳食和静脉注射的反应）葡萄糖推注），以及 3）24 小时葡萄糖和游离脂肪酸 (FFA) 稳态（通过测量 24 小时内的葡萄糖和 FFA 浓度和动力学进行评估） h) 患有 T2D 的肥胖受试者（体重指数 35-55 kg/m2） 此外，我们将研究可能对减肥治疗有可测量的有益反应的 T2D 受试者（即 T2D 持续时间 <10 的受试者）。年龄，血糖控制合理，并且没有接受胰岛素治疗），以提高我们检测手术和饮食疗法之间潜在差异的能力，我们认为，与 LCD 疗法引起的相同体重减轻相比， RYGB 将导致：i) 肝脏而非骨骼肌胰岛素敏感性的更大改善；ii) 根据摄入葡萄糖而非静脉注射葡萄糖评估的 β 细胞功能的更大改善；以及 iii) 24 小时血糖和 FFA 的更大改善该项目将回答 RYGB 对 T2D 患者体重大幅减轻后调节血糖控制的代谢过程是否具有临床上重要的独立于体重减轻的影响的问题。具有生理和医学重要性，并将有助于确定未来研究的特定代谢目标。