Effect of Bariatric Surgery on Mechanisms of Type 2 Diabetes: The B2D Trial

描述(申请人提供)：本申请是对RFA-DK-09-012：减肥手术后2型糖尿病改善机制和心血管危险因素的初步研究的回应。目前的估计表明，11.3%的美国人口患有2型糖尿病，在美国许多州，超过30%的人口患有肥胖症。确定肥胖症和2型糖尿病的有效治疗方法显然是公共卫生的迫切需要。Roux-en-Y胃分流术(RYGB)代表了一种治疗方法，可以产生长期的体重减轻，并可能导致T2 DM的完全解决；这种发现对这种顽固性疾病的治疗具有特殊的意义。RYGB是一种减肥手术，包括将上胃缝合，将胃容量减少到15-30毫升，并绕过剩余的胃、十二指肠和一小部分空肠。我们和其他人已经证明，胃旁路手术对体重减轻、2型糖尿病的解决有显著的长期效果，并对极端肥胖患者的心血管危险因素有积极影响。这项申请的目的是评估RYGB手术对中度肥胖(BMI：30-40 kg/m2)受试者的血糖控制和导致2型糖尿病的潜在机制的影响。我们的中心假设是，RYGB手术将通过逆转β细胞功能障碍和降低肝脏和外周胰岛素抵抗来降低高血糖。具体目标是：1)开发和实施一项为期12个月的前瞻性随机对照临床试验，以测试胃旁路手术与先进的药物治疗和生活方式对60名2型糖尿病肥胖患者血糖控制的影响；2)确定胃旁路手术对胰岛β细胞功能和胰岛素激素分泌的影响；以及3)对胰岛素敏感性、异位脂肪堆积和骨骼肌细胞信号的影响。主要的结果变量是12个月时HbA1c为6.5%。混合膳食耐量试验将使用胰岛素/C肽动力学建模方法来评估β细胞功能的变化；正常血糖高胰岛素钳夹将用于评估胰岛素敏感性。此外，还将通过测量胰岛素激素反应(GLP-1/GIP)、利用磁共振波谱测量肝脏和骨骼肌中的脂肪积累，以及调节骨骼肌中葡萄糖摄取的胰岛素信号通路来探索潜在的机制。从拟议的研究中产生的数据将促进我们对胰腺、肝脏和骨骼肌代谢功能障碍与2型糖尿病之间联系的生理机制的理解，以及减肥手术后的解决办法。拟议的试验还将提供重要的初步数据，为长期试验的招募、保留、随访和程序提供信息，该试验将比较手术和先进的药物治疗，因为我们努力确定对抗2型糖尿病的最佳治疗策略。

DESCRIPTION (provided by applicant): This application is in response to RFA-DK-09-012: Pilot Studies for Studying the Mechanisms of Improvement in Type 2 Diabetes and Cardiovascular Risk Factors after Bariatric Surgery. Current estimates indicate that 11.3% of the US population have type 2 diabetes and in many US states over 30% of the population are obese. The identification of effective therapies for obesity and type 2 diabetes is clearly an urgent public health need. Roux- en-Y gastric bypass (RYGB) surgery represents a therapeutic approach that produces long term weight loss and may lead to the complete resolution of T2DM; such a finding holds exceptional significance for the management of this recalcitrant disease. RYGB is a bariatric procedure that involves stapling the upper stomach to reduce stomach capacity to 15-30 mls and bypassing the remaining stomach, duodenum and a small portion of the jejunum. We and others have shown that gastric bypass surgery has significant long-term effects on weight loss, the resolution of type 2 diabetes, and has a positive effect on cardiovascular risk factors in extremely obese patients. The objective of this application is to evaluate the effects of RYGB surgery on glycemic control and underlying mechanisms that contribute to type 2 diabetes in moderately obese subjects (BMI: 30-40 kg/m2). Our central hypothesis is that RYGB surgery will reduce hyperglycemia by reversing beta-cell dysfunction and decreasing hepatic and peripheral insulin resistance. The Specific Aims are: 1) to develop and implement a 12-month prospective randomized controlled clinical trial to test the effect of gastric bypass surgery versus advanced medical therapy and lifestyle on glycemic control in 60 obese patients with type 2 diabetes; 2) to determine the effects of gastric bypass surgery on pancreatic beta-cell function and incretin hormone secretion; and 3) effects on insulin sensitivity, ectopic lipid accumulation, and cellular signaling in skeletal muscle. The primary outcome variable is an HbA1c of d 6.5% at 12 months. Mixed meal tolerance tests will be used to assess changes in beta-cell function using an insulin/C-peptide kinetic modeling approach; and euglycemic hyperinsulinemic clamps will be used to evaluate insulin sensitivity. In addition, the underlying mechanisms will be explored by measuring incretin hormone responses (GLP-1/GIP), lipid accumulation in the liver and skeletal muscle using magnetic resonance spectroscopy, and insulin signaling pathways that regulate glucose uptake in skeletal muscle. The data that will be generated from the proposed studies will advance our understanding of the physiological mechanisms that link metabolic dysfunction in the pancreas, liver, and skeletal muscle with type 2 diabetes, and its resolution following bariatric surgery. The proposed trial will also provide important preliminary data to inform recruitment, retention, follow-up, and procedures for a longer-term trial that will compare surgery with advanced medical therapy, as we strive to identify the optimal treatment strategy to counter type 2 diabetes