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（T2 D）是肥胖症的主要并发症，由多器官胰岛素抵抗和胰腺胰岛素分泌不足引起。患有T2 D的肥胖人群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）。减肥手术导致体重明显减轻，是T2 D最有效的治疗方法。此外，已经提出，绕过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不依赖于体重减轻的效果。尽管RYGB手术对口服葡萄糖或膳食摄入的代谢反应具有深远影响是清楚的，但仍不清楚RYGB是否对T2 D患者中负责糖尿病缓解的关键因素（即β细胞功能、胰岛素敏感性以及整合的24小时葡萄糖和脂肪酸稳态）具有长期的、临床上重要的、不依赖于体重减轻的影响。在体重明显减轻之后。因此，本提案的总体目标是仔细解决肥胖T2 D受试者的这些问题。因此，我们将评估由RYGB手术或低热量饮食（LCD）诱导的16%-18%体重减轻（与能量摄入和体重减轻率相匹配）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-正常血糖胰腺钳夹程序，并通过评价响应于混合膳食摄入的内源性葡萄糖产生的抑制来评估），2）β-细胞功能（即胰岛素分泌和处置指数;在对口服混合餐和静脉内葡萄糖推注的反应中评估），和3）肥胖（体重指数35-55 kg/m2）T2 D受试者的24小时葡萄糖和游离脂肪酸（FFA）稳态（通过测量24小时内的葡萄糖和FFA浓度和动力学评估）。此外，我们将研究可能对减肥治疗有可测量的有益反应的T2 D受试者（即T2 D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治疗诱导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）对摄入葡萄糖而非静脉内葡萄糖的反应评估的β细胞功能的更大改善; iii）24小时葡萄糖和FFA代谢的更大改善。该项目将回答以下问题：RYGB是否对T2 D患者体重减轻相当多后调节血糖控制的代谢过程具有临床重要的体重减轻独立作用。这项研究的结果具有生理和医学重要性，将有助于确定未来研究的特定代谢目标。

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.