Youth-onset type 2 diabetes (T2D) leads to early dependence on exogenous insulin and progression of T2D co-morbidities, including dyslipidemia, hypertension, non-alcoholic fatty liver disease and diabetic kidney dis- ease. The pathophysiology of T2D in youth differs considerably from adults and current treatment approaches are inadequate for youth. Thus, exploration of innovative approaches to reduce co-morbidities is critical. Meta- bolic bariatric surgery (MBS) significantly improves multiple outcomes in adults with T2D. Initial small, uncon- trolled studies of Roux-en-Y gastric bypass also suggest beneficial effects in youth with T2D, but definitive studies and understanding of mechanisms in youth-onset T2D are lacking, especially with the now more com- mon form of MBS, vertical sleeve gastrectomy (VSG). Our long-term goal is to improve the treatment of youth- onset T2D to reduce morbidity and mortality. Our central hypothesis is that VSG will be more effective in reduc- ing glycemia and comorbidities than the best currently available medical treatment: advanced medical therapy (AMT), via pancreatic, enterohepatic and/or metabolic changes. To test this hypothesis, we will enroll 90 ado- lescents with T2D across two sites and compare the effects of VSG vs. AMT on glycemic control and T2D-as- sociated comorbidities, as well as underlying mechanisms. Our sites have collaborative pediatric medical and surgical expertise, including use of non-invasive metabolic measures in MBS and T2D and collectively have a large, diverse adolescent T2D cohort, making us uniquely positioned to accomplish these aims. Our rationale is that 1) there is a critical need to determine the impact of VSG over AMT in youth-onset T2D, and 2) im- proved knowledge of the mechanisms underlying the impact of MBS will direct future non-surgical approaches to mimic MBS less invasively.
Aim 1 will evaluate the effects of VSG vs. AMT on glycemic control and T2D- associated co-morbidities. We hypothesize that a higher proportion of youth with T2D receiving VSG vs. AMT will achieve the primary endpoint of HbA1c <6% with higher rates of remission (lower incidence) of comorbidi- ties at 1 and 2 years. We will also explore the impact of T2D duration, BMI, sex and initial HbA1c on the pri- mary outcome.
Aim 2 will elucidate mechanisms by which VSG & AMT influence pancreatic islet cell function, enterohepatic metabolism and tissue-specific insulin sensitivity, and their contributions to glycemic control in youth with T2D. We hypothesize that the primary outcome of ?-cell function will improve in T2D youth undergo- ing VSG vs. AMT at 1 and 2 years. Secondary endpoints include whole-body IR, tissue-specific IR, incretin re- sponse and ?-cell function to understand mechanisms underlying improvements. These results will determine whether MBS is more effective than AMT in promoting glycemic control and reducing co-morbidities in youth- onset T2D, an outcome that would dramatically improve the lives of youth who currently have a dismal progno- sis. Further, this proposal will help understand the mechanisms underlying MBS in youth, to guide the develop- ment of future treatments that could target these same pathways without the need for surgery.
Youth-onset type 2 diabetes (T2D) differs in pathophysiology from T2D in adults and current treatment op- tions are inadequate often leads to rapid dependence on exogenous insulin and early development of co-mor- bidities, demanding innovative approaches. Metabolic bariatric surgery (MBS) significantly improves multiple T2D outcomes in adults and preliminary data from Roux-en-Y gastric bypass suggest beneficial effects in T2D youth, but definitive studies in youth with T2D are lacking, especially with the now more common form of MBS, vertical sleeve gastrectomy (VSG). This proposal by a highly experienced group will test the hypothesis that VSG will more effectively provide glycemic control and co-morbidity reduction than intensive medical therapy in youth with T2D, and will explore the mechanisms underlying VSG, in order to improve current care for youth with T2D.
