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

描述（由申请人提供）：虽然越来越多的文献证明了减肥手术对2型糖尿病（T2DM）预后的初步益处，但很少有研究报道了受试者内T2DM缓解的长期纵向结果。在为数不多的患者中，估计两年后T2DM缓解的患者在腹腔镜可调节绑扎术后为17%，在Roux-en-Y胃旁路手术（GBP）后为75%。减肥手术后10年，T2DM的发病率再次从2%（2年后）上升到7%，尽管这仍然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，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是很重要的。迄今为止，确定的因素包括术前T2DM病程、术前血糖控制较好、术后初期和长期体重减轻。T2DM手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。这类患者往往表现为胰岛素分泌能力恶化，同时出现胰岛素抵抗。因此，本项目的目的是研究GBP后T2DM患者葡萄糖稳态持续改善的生理机制。作为减肥手术（实验室）糖尿病亚研究的纵向评估的一部分，我们招募并研究了39名患有T2DM的受试者和22名没有T2DM的受试者，这些受试者在性别、年龄和基线体重指数（BMI）方面与较大的实验室队列相匹配。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，这些数据均与饮食相关和静脉注射葡萄糖有关。我们的数据证实了我们的预测，我们将发现两组之间胰岛细胞分泌反应恢复的差异，表明T2DM患者在GBP后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术后糖尿病和糖耐量状况改善的机制，但在长期术后随访中，关于患者高血糖和2型糖尿病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，恰逢稳定期前典型的体重小幅回升。我们将利用在母公司实验室试验中获得的扩展临床和表型数据库来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

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.