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

描述（由申请人提供）：虽然大量且不断增长的文献证明了减肥手术对2型糖尿病（T2 DM）结局的初步获益，但很少有研究报告了T2 DM缓解的受试者内长期纵向结果。在少数患者中，2年后T2 DM缓解的估计值范围从腹腔镜可调节束带术后的17%到接受Roux-en-Y胃旁路手术（GBP）的75%。减肥手术后10年，T2 DM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的24%发病率。对于临床决策，重要的是确定与减肥手术后的初始血糖反应和T2 DM缓解的持久性相关或可预测的患者特征。迄今为止，确定的因素包括术前T2 DM的持续时间、术前血糖控制更好以及术后初始和长期体重减轻。T2 DM术前持续时间较长和血糖控制较差对缓解和持久性的预测潜力的机制解释与这些因素与胰岛分泌能力的关系有关。这类患者通常表现出恶化的胰岛素分泌能力，同时胰岛素抵抗。因此，本项目的目标是检查有助于GBP后T2 DM葡萄糖稳态持续改善的生理机制。作为减肥手术（LABS）糖尿病子研究纵向评估的一部分，我们入组并研究了来自较大LABS队列的39例T2 DM受试者和22例非T2 DM受试者，这些受试者在性别、年龄和基线体重指数（BMI）方面匹配。我们获得了基线、6个月和2年的胰岛素敏感性和胰岛细胞分泌反应的数据，这些数据使用了膳食相关和静脉内葡萄糖激发。我们的数据证实了我们的预测，即我们将发现两组之间在胰岛细胞分泌反应恢复方面的差异反应，表明GBP后T2 DM患者的胰岛细胞分泌能力得到更大改善。虽然这些数据有助于解决GBP后糖尿病和葡萄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症和T2 DM复发风险的生理机制仍存在问题。因此，我们现在建议继续研究这些手术后5年和9年的良好特征的受试者，这与平稳期前典型的小体重恢复一致。我们将利用母实验室试验期间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一个关键的 我们目前对减肥手术后糖尿病缓解或胰岛素抵抗和T2 DM复发的长期持久性机制的理解有限。

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.