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（T2DM）的重要危险因素，是美国主要的公共卫生问题。减肥手术是目前治疗肥胖最有效的减肥方法。此外，Roux-en-Y胃旁路术（RYGB）在美国和世界范围内是最常用的减肥手术，约80%的患者的T2DM得到缓解。有研究表明，RYGB手术前T2DM诊断的持续时间是糖尿病解决的预测指标。然而，这一假设从未在人类受试者中得到充分的评估。因此，本研究的主要目的是为了更好地了解减肥手术对胰岛素作用和胰腺细胞功能的影响，因为它与T2DM诊断的持续时间有关（近期与长期）。我们假设RYGB手术提供的体重减轻对新近诊断为T2DM的严重肥胖患者的胰岛素敏感性和¿-细胞功能的影响大于长期疾病患者。在两组接受RYGB手术的重度肥胖T2DM患者中，将评估以下具体目标：1)“新近”诊断T2DM的肥胖患者（5年）和2)“长期”T2DM的肥胖患者（10年）。代谢研究将在RYGB之前进行，并在受试者减去总体重的20%后重复进行。具体来说，我们的目标是：1。评估RYGB后减肥对胰岛素在肝脏（抑制葡萄糖生成）、骨骼肌（刺激葡萄糖摄取）和脂肪组织（抑制脂肪分解）中的作用的影响。这一目标将通过两阶段高胰岛素正糖钳夹手术进行评估，并结合稳定的同位素标记示踪剂输注。和2。评价RYGB诱导的减肥对胰腺细胞反应的影响。这一目标将通过进行混合膳食耐量试验（MMTT）来评估，并结合稳定同位素示踪剂的摄入和输注，以评估摄入葡萄糖的吸收、内源性葡萄糖产生的抑制以及对膳食的胰岛素分泌。这些目标的实现将为减肥（RYGB）手术对T2DM的影响提供重要的生理和临床知识，因为它与这种疾病的持续时间有关。这项研究的成功完成可能会影响目前选择减肥手术患者的临床指南。这些目标的实现将为减肥（RYGB）手术对T2DM的影响提供重要的生理和临床知识，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根据病程选择T2DM患者进行减肥手术的临床实践指南。

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.