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）：虽然越来越多的文献证明减肥手术对 2 型糖尿病 (T2DM) 结局具有初步益处，但很少有研究报告受试者内 T2DM 缓解的长期纵向结果。在少数接受过治疗的患者中，两年后 T2DM 缓解的估计范围从腹腔镜可调节束带术后的 17% 到接受 Roux-en-Y 胃绕道手术 (GBP) 的患者的 75%。减肥手术十年后，T2DM 的发病率再次从 2%（2 年后）上升至 7%，尽管这仍远低于尝试药物减肥的匹配对照组 24% 的发病率。对于临床决策而言，确定与减肥手术后初始血糖反应和 T2DM 缓解持久性相关或可预测的患者特征非常重要。迄今为止，已确定的因素包括术前 T2DM 持续时间、更好的术前血糖控制以及术后初始和长期体重减轻。 T2DM 较长的术前持续时间和较差的血糖控制对缓解和持久性的预测潜力的机制解释涉及这些因素与胰岛分泌能力的关系。此类患者通常表现出胰岛素分泌能力恶化，同时出现胰岛素抵抗。因此，该项目的目标是检查 GBP 后有助于持续改善 T2DM 葡萄糖稳态的生理机制。作为减肥手术纵向评估 (LABS) 糖尿病子研究的一部分，我们招募并研究了来自较大 LABS 队列的 39 名患有 T2DM 的受试者和 22 名未患有 T2DM 的受试者，这些受试者的性别、年龄和基线体重指数 (BMI) 相匹配。我们使用膳食相关和静脉注射葡萄糖挑战获得了胰岛素敏感性和胰岛细胞分泌反应的基线、6 个月和 2 年数据。我们的数据证实了我们的预测，即我们将发现各组之间在胰岛细胞分泌反应恢复方面存在差异反应，表明 GBP 后 T2DM 患者的胰岛细胞分泌能力有更大的改善。虽然这些数据有助于解决 GBP 后糖尿病和糖耐量状态改善的机制，但关于患者在长期术后随访期间高血糖和 T2DM 复发风险的生理机制仍然存在疑问。因此，我们现在建议在手术后 5 年和 9 年继续研究这些特征明确的受试者，这与平台期前典型的小幅体重反弹相一致。我们将利用在母实验室试验期间获得的扩展临床和表型数据库来补充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 我们目前对减肥手术后糖尿病长期缓解或胰岛素抵抗和 T2DM 复发机制的理解存在局限性。