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

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的肥胖者的体重减轻可以改善胰岛素分泌和胰岛素作用，甚至导致完全缓解(没有糖尿病药物的正常血糖控制)。减肥手术可以显著减轻体重，是治疗T2D的最有效的治疗方法。此外，有人提出，在实现血糖控制方面，绕过上胃肠道的外科手术，如Roux-en-Y胃搭桥术(RYGB)，在实现血糖控制方面具有独立的减肥效果。虽然RYGB手术对口服葡萄糖或进食食物的代谢反应有深远的影响，但在显著减肥后，RYGB是否对导致T2D患者糖尿病缓解的关键因素，即β细胞功能、胰岛素敏感性和整合的24小时血糖和脂肪酸稳态，具有长期的、临床重要的、非减肥作用尚不清楚。因此，这项建议的总体目标是用T2D仔细地解决肥胖受试者的这些问题。因此，我们将评估RYGB手术或低热量饮食(能量摄入和体重减少率匹配)导致的16%-18%体重下降对以下方面的影响：1)肝脏和骨骼肌胰岛素敏感性(通过使用高胰岛素-正常血糖胰腺钳手术，以及通过评估对混合膳食摄入内源性葡萄糖的抑制)，2)β细胞功能(即胰岛素分泌和处置指数；3)肥胖(体重指数35-55 kg/m2)受试者的24小时葡萄糖和游离脂肪酸(FFA)稳态(通过测量24小时内葡萄糖和游离脂肪酸的浓度和动力学来评估)。此外，我们将研究T2D受试者，这些受试者可能对减肥治疗有可测量的有益反应(即，那些持续T2D&lt；10年、血糖控制合理、没有接受胰岛素治疗的人)，以提高我们发现手术和饮食治疗之间潜在差异的能力。我们假设，与液晶治疗的相同体重减轻相比，RYGB将导致：i)肝脏而不是骨骼肌对胰岛素的敏感性有更大的改善；ii)对摄入葡萄糖而不是静脉葡萄糖的β细胞功能有更大的改善；iii)24小时葡萄糖和游离脂肪酸代谢有更大的改善。这个项目将回答RYGB是否具有临床上重要的减肥作用--在T2D患者体重减轻相当多后，对调节血糖控制的代谢过程是否具有独立的影响。这项研究的结果具有重要的生理和医学意义，将有助于为未来的研究确定特定的代谢靶点。

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 β-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) β-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 β-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.