LABS Sub-study: Mechanisms of Durability of Type 2 Diabetes Remission

LABS 子研究：2 型糖尿病缓解持久机制

• 批准号: 8800570
• 负责人: JONATHAN Q. PURNELL
• 金额: $ 34.81万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800570
• 关键词: Activities of Daily Living; Acute; Address; Age; Bile Acids; Blood specimen; Body Weight; Body Weight decreased; Body mass index; Branched-Chain Amino Acids; C-Peptide; Cell physiology; Cells; Characteristics; Clinical; Collaborations; Control Groups; Data; Databases; Deterioration; Development; Diabetes Mellitus; Disease remission; Enrollment; Exhibits; Fasting; Fatty Acids; GNAI2 gene; Gastric Bypass; Glucagon; Glucose; Glucose tolerance test; Goals; Hormones; Hyperglycemia; Incidence; Individual; Ingestion; Insulin; Insulin Resistance; Intestines; Intravenous; Islet Cell; Lead; Literature; Long-Term Effects; Measures; Medical; Metabolic; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Parents; Patients; Physiological; Postoperative Period; Prevention; Proinsulin; Recovery; Recurrence; Reporting; Risk; Sampling; Taurine; Testing; Therapeutic Agents; Time; Visit; Weight; bariatric surgery; blood glucose regulation; clinical decision-making; cohort; des-n-octanoyl ghrelin; follow-up; ghrelin; glucagon-like peptide 1; glucose metabolism; glucose tolerance; glycemic control; incretin hormone; insight; insulin secretion; insulin sensitivity; islet; metabolomics; novel therapeutics; operation; pancreatic islet function; public health relevance; response; sex

DESCRIPTION (provided by applicant): While a large and growing body of literature attests to the initial benefits of bariatric surgery on type 2 diabetes (T2DM) outcomes, a paucity of studies have reported within-subject, long-term longitudinal results of T2DM remission. Of the few that have, estimates of T2DM remission after two years have ranged from 17% after laparoscopic adjustable banding to 75% of patients undergoing Roux-en-Y gastric bypass surgery (GBP). Ten years after bariatric surgery, the incidence of T2DM rises again from 2% (after 2 years) to 7%, though this is still well below the 24% incidence rate in the matched control group attempting medical weight loss. For clinical decision making, it will be important to identify patient characteristics that are associated with, or predictive of, the initial glycemic response and durability of T2DM remission following bariatric surgery. To date, identified factors include duration of T2DM before surgery, better presurgical glycemic control, and initial and long-term post-op weight loss. Mechanistic explanations for the predictive potential of a longer presurgical duration of T2DM and poorer glycemic control on remission and durability pertains to the relationship of these factors to islet secretory capacity. Such patients often exhibit worsened insulin secretory capacity while insulin resistant. Therefore, the goal of this project is to examie the physiological mechanisms that contribute to sustained improvements of glucose homeostasis in T2DM following GBP. As part of the Longitudinal Assessment of Bariatric Surgery (LABS) Diabetes sub study, we enrolled and studied 39 subjects with, and 22 subjects without, T2DM, matched for sex, age, and baseline body mass index (BMI) from the larger LABS cohort. We obtained baseline, 6-month, and 2-year data on insulin sensitivity and islet cell secretory responses using both meal-related and intravenous glucose challenges. Our data confirmed our prediction that we would find a differential response in terms of islet cell secretor response recovery between the groups demonstrating greater improvement in islet cell secretory capacity in those with T2DM after GBP. While these data help address the mechanisms responsible for improvement in diabetes and glucose tolerance status following GBP, questions remain regarding the physiological mechanisms underlying a patient's risk for recurrence of hyperglycemia and T2DM during long-term post-operative follow-up. Therefore, we now propose to continue to study these well characterized subjects 5 and 9 years after their surgeries, coinciding with a typical small weight regain before plateauing. We will take advantage of the extended clinical and phenotypic database obtained during the parent LABS trial to add to our detailed studies of glucose metabolism. These data will help fill in a critical limitation of our current understanding of the mechanisms of long-term durability of diabetes remission or recurrence of insulin resistance and T2DM after bariatric surgery.

描述（由申请人提供）：虽然大量的文献证明了减肥手术对2型糖尿病（T2DM）结果的最初益处，但大量研究报告了T2DM缓解的长期纵向结果。在少数具有腹腔镜可调式带后的T2DM缓解量的估计中，T2DM缓解量的范围从17％到接受Roux-en-Y-Y胃旁路手术（GBP）的75％的患者。减肥手术十年后，T2DM的发病率从2％（2年后）再次上升到7％，尽管这仍然远低于试图减肥的匹配对照组的24％发病率。对于临床决策，重要的是确定与减肥手术后T2DM缓解的初始血糖反应和耐用性相关的患者特征。迄今为止，确定的因素包括手术前T2DM的持续时间，更好的前血糖控制以及初始和长期的手术后体重减轻。 T2DM前术前持续时间较长的预测潜力和较差的血糖控制对这些因素与胰岛分泌能力的关系的机理解释。这些患者在胰岛素耐药性的同时经常表现出恶化的胰岛素分泌能力。因此，该项目的目的是检查GBP后T2DM中葡萄糖稳态持续改善的生理机制。作为减肥手术纵向评估（LABS）糖尿病SUB研究的一部分，我们招募并研究了39名受试者，而没有T2DM的22名受试者，与较大实验室的性别，年龄和基线体重指数（BMI）相匹配。我们使用与餐食相关的葡萄糖挑战和胰岛素葡萄糖挑战获得了有关胰岛素敏感性和胰岛细胞分泌反应的基线，6个月和2年的基线数据。我们的数据证实了我们的预测，即我们在胰岛细胞分泌剂的响应恢复方面发现了差异反应，这表明在GBP后具有T2DM的胰岛细胞分泌能力上有更大的改善。尽管这些数据有助于解决负责改善糖尿病和葡萄糖耐量状况的机制，但在长期术后随访期间，患者在长期术后患者复发高血糖和T2DM风险的生理机制仍然存在问题。因此，我们现在建议在手术后5年和9年继续研究这些良好的受试者，与典型的小重量重新获得平稳之前的重量相吻合。我们将利用在父型实验室试验中获得的扩展临床和表型数据库，以增加我们对葡萄糖代谢的详细研究。这些数据将有助于填补关键 我们目前对糖尿病缓解长期耐用性或胰岛素抵抗和T2DM复发的机制的限制。