EFFECTS OF BARIATRIC SURGERY ON GLUCOSE HOMEOSTASIS IN TYPE-2 DIABETES

描述（由申请人提供）：肥胖是2型糖尿病（T2 DM）的重要风险因素，2型糖尿病是美国的主要公共卫生问题。减肥手术是目前治疗肥胖最有效的减肥疗法。此外，Roux-en-Y胃旁路术（RYGB）是美国和全球最常进行的减肥手术，约80%的患者的T2 DM消退。研究表明，RYGB手术前T2 DM诊断的持续时间是糖尿病消退的预测因素。然而，这一假设从未在人类受试者中得到充分评价。因此，本提案的主要目的是更好地了解减肥手术诱导的体重减轻对胰岛素作用和胰腺细胞功能的影响，因为它与T2 DM诊断的持续时间有关（近期与长期）。我们假设RYGB手术所提供的体重减轻对最近诊断为T2 DM的严重肥胖患者的胰岛素敏感性和胰岛细胞功能的影响大于长期患病的患者。将在接受RYGB手术的两组重度肥胖T2 DM患者中评价以下特定目标：1）“近期”诊断为T2 DM的肥胖患者（d> 5年）和2）“长期”T2 DM的肥胖患者（e> 10年）。代谢研究将在RYGB前进行，并在受试者体重减轻约20%后重复进行。具体而言，我们的目标是：1。评价RYGB后体重减轻对肝脏（抑制葡萄糖产生）、骨骼肌（刺激葡萄糖摄取）和脂肪组织（抑制脂解）中胰岛素作用的影响。这一目标将通过进行两阶段高胰岛素正葡萄糖钳夹程序，结合稳定的同位素标记示踪剂输注进行评价。和2.评价RYGB诱导的体重减轻对胰腺细胞反应的影响。将通过进行混合膳食耐受性试验（MMTT）并结合稳定同位素示踪剂摄入和输注来评价这一目标，以评估摄入葡萄糖的吸收、内源性葡萄糖产生的抑制和对膳食的胰岛素分泌反应。这些目标的实现将提供关于减肥（RYGB）手术对T2 DM影响的重要生理和临床知识，因为它与这种疾病的持续时间有关。本研究的成功完成可能会影响目前的临床指南，选择患者进行减肥手术。这些目标的实现将提供关于减肥（RYGB）手术对T2 DM影响的重要生理和临床知识，因为它与这种疾病的持续时间有关。这项研究的结果可能会影响目前的临床实践指南，根据疾病的持续时间选择T2 DM患者进行减肥手术。 公共卫生相关性：肥胖是2型糖尿病（T2 DM）的一个重要危险因素，T2 DM是美国的一个主要公共卫生问题。减肥手术是目前治疗肥胖最有效的减肥疗法，约80%的T2 DM患者可以通过减肥手术缓解。我们的目的是确定手术诱导的体重减轻对葡萄糖代谢的影响，因为它与T2 DM诊断的持续时间有关（近期与长期）。

DESCRIPTION (provided by applicant): Obesity is an important risk factor for type 2 diabetes mellitus (T2DM), which is a major public health problem in the U.S. Bariatric surgery is currently the most effective weight loss therapy for obesity. Furthermore, Roux-en-Y gastric bypass (RYGB) is most commonly performed bariatric procedure in the US and worldwide and results in resolution of T2DM in ~80% of patients. It has been suggested that the duration of T2DM diagnosis before RYGB surgery is a predictor for diabetes resolution. However, this hypothesis has never been adequately evaluated in human subjects. Therefore, the primary purpose of this proposal is to provide a better understanding of the effect of bariatric surgery-induced weight loss on insulin action and pancreatic ¿-cell function as it relates to the duration of T2DM diagnosis (recent vs. longstanding). We hypothesize that the weight loss provided by RYGB surgery will have greater effects on insulin sensitivity and ¿ -cell function in severely obese wit recently diagnosed T2DM than those with longstanding disease. The following specific aims will be evaluated in two groups of severely obese patients with T2DM undergoing RYGB surgery: 1) obese patients with "recently" diagnosed T2DM (d 5 years) and 2) obese patients with "longstanding" T2DM (e 10 years). Metabolic studies will be performed before RYGB and repeated after subjects have lost ~ 20% of total body weight. Specifically we aim to: 1. Evaluate the effect of weight loss after RYGB on insulin action in liver (suppression of glucose production), skeletal muscle (stimulation of glucose uptake) and adipose tissue (suppression of lipolysis). This aim will be evaluated by conducting a two-stage hyperinsulinemic euglycemic clamp procedure, in conjunction with stable isotopically-labeled tracer infusion. and 2. Evaluate the effect of RYGB induced weight loss on pancreatic ¿-cell response. This aim will be evaluated by conducting a Mixed Meal Tolerance Test (MMTT), in conjunction with stable isotope tracer ingestion and infusion, to assess absorption of ingested glucose, suppression of endogenous glucose production, and insulin secretion in response to the meal. The achievement of these aims will provide important physiological and clinical knowledge regarding the effect of bariatric (RYGB) surgery on T2DM as it relates of the duration of this condition. Successful completion of this study could influence the current clinical guidelines for the selection of patients for bariatric surgery. The achievement of these aims will provide important physiological and clinical knowledge regarding the effect of bariatric (RYGB) surgery on T2DM as it relates of the duration of this condition. The results from this study could influence curren clinical practice guidelines for the selection of patients who have T2DM for bariatric surgery based on the duration of disease. PUBLIC HEALTH RELEVANCE: Obesity is an important risk factor for type 2 diabetes mellitus (T2DM), which is a major public health problem in the U.S. Bariatric surgery is currently the most effective weight loss therapy for obesity that results in resolution of T2DM in ~80% of patients. We aim to determine the effects of surgical induced weight loss on glucose metabolism as it relates to the duration of T2DM diagnosis (recent vs. longstanding).