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

描述（由申请人提供）：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。肥胖的t2dm患者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）。减肥手术能显著减轻体重，是治疗糖尿病最有效的方法。此外，有人提出，旁路上胃肠道的外科手术，如roux-en-Y胃旁路术（RYGB），在实现血糖控制方面具有独立于体重减轻的效果。虽然已经清楚RYGB手术对口服葡萄糖或膳食摄入的代谢反应有深远的影响，但仍不清楚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24小时葡萄糖和脂肪酸的综合稳态，具有长期的、临床重要的、不依赖于体重减轻的影响。因此，本提案的总体目标是仔细解决肥胖t2dm患者的这些问题。因此，我们将评估RYGB手术或低热量饮食（LCD）引起的16%-18%的体重减轻对以下方面的影响：1)肝脏和骨骼肌胰岛素敏感性（通过使用高胰岛素-正血糖胰腺钳夹手术评估，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；3)肥胖（体重指数35-55 kg/m2） T2D患者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浓度和动力学）。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年，血糖控制合理，未接受胰岛素治疗的受试者），以提高我们检测手术和饮食治疗之间潜在差异的能力。我们假设，与LCD治疗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) β细胞功能在摄入葡萄糖而非静脉注射葡萄糖的情况下有更大的改善；iii) 24小时葡萄糖和游离脂肪酸代谢有较大改善。该项目将回答RYGB是否在临床上对t2dm患者体重减轻后调节血糖控制的代谢过程具有重要的减肥无关作用的问题。这项研究的结果具有生理学和医学意义，并将有助于确定未来研究的特定代谢靶点。

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.