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)结果的初步好处，但很少有研究报告受试者内T2 DM缓解的长期纵向结果。在少数有此症状的患者中，估计两年后T2 DM的缓解率从腹腔镜可调捆扎术后的17%到接受Roux-en-Y胃旁路手术(GBP)的75%不等。减肥手术十年后，T2 DM的发病率再次从2%(两年后)上升到7%，尽管这仍然远低于试图通过药物减肥的匹配对照组24%的发病率。对于临床决策，重要的是确定与减肥手术后T2 DM缓解的初始血糖反应和持久性相关的或预测的患者特征。到目前为止，已确定的因素包括手术前T2 DM的持续时间，较好的术前血糖控制，以及手术后的初始和长期体重减轻。对T2 DM术前病程较长和血糖控制较差对缓解和耐受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。这类患者在胰岛素抵抗时，通常表现出胰岛素分泌能力恶化。因此，本项目的目标是研究GBP后T2 DM患者血糖稳态持续改善的生理机制。作为减肥手术纵向评估(LABS)糖尿病子研究的一部分，我们从较大的实验室队列中招募并研究了39名患有T2 DM的受试者和22名非T2 DM的受试者，这些受试者的性别、年龄和基线体重指数(BMI)都是匹配的。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，包括进餐相关和静脉血糖挑战。我们的数据证实了我们的预测，即我们将在胰岛细胞分泌反应恢复方面发现不同组之间的差异，这些组在GBP后表现出更大的胰岛细胞分泌能力改善。虽然这些数据有助于解决GBP术后糖尿病和糖耐量状态改善的机制，但关于患者在术后长期随访期间复发高血糖和T2 DM的潜在生理机制仍存在疑问。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良好的受试者，同时在平台期之前出现典型的小体重回升。我们将利用在母公司实验室试验期间获得的扩展的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写关键的 目前我们对减肥手术后糖尿病缓解或胰岛素抵抗复发和T2 DM长期持久性机制的认识存在局限性。

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.