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.
Studies in this proposal will provide new insight into the clinical and physiological mechanisms that determine long-term durability of remission or recurrence of type 2 diabetes mellitus following weight loss after a gastric bypass operation. Understanding these factors could not only potentially lead to development of new therapeutic agents for diabetes but could also be important for clinical decision making in determining the optimal patient in the consideration of bariatric surgery for the treatment of type 2 diabetes.