Effect of adiposity on hepatic and peripheral insulin resistance and hepatic steatosis in pubertal adolescents with type 1 diabetes

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PROJECT SUMMARY/ABSTRACT The purpose of this research study is to elucidate how the insulin resistance of obesity affects glucose and fat metabolism and hepatic fat deposition in pubertal adolescents with type 1 diabetes (T1D). With improved glycemic control and increased rates of obesity nationally, obesity is now prevalent in youth with T1D. Understanding how obesity affects metabolism in T1D has implications for treatment decisions. This knowledge will provide insights into potential adjunctive therapy interventions that may be applied in the future to improve insulin resistance and mitigate weight gain, both which would vastly thus improve management of T1D patients who have obesity. The specific aims of this project are to assess the effects of adiposity and puberty on resistance to insulin's ability to suppress hepatic glucose production, stimulate peripheral glucose metabolism, and suppress rates of lipolysis in pubertal youth with T1D and to examine the role of fatty liver disease on insulin resistance in adolescents with obesity and T1D. The first aim will be conducted using the stepped, hyperinsulinemic- euglycemic glucose clamp technique with stable isotope tracer infusions to assess changes in endogenous glucose production, peripheral glucose uptake, and glycerol turnover in response to graded increases in rates of insulin infusion. The second aim will assess the impact of fatty liver disease and fat distribution on the insulin resistance of obesity in adolescents with T1D using abdominal MRI. The clamp and MRI studies will be carried out in 36 obese and 36 lean pubertal adolescents with T1D and the clamp study will also include 36 lean young adults with T1D. Carrying out the proposed program of research and analyzing the results, under the guidance of my outstanding mentorship team, will further my development into an independent pediatric physician-scientist. I will gain expertise in sophisticated measures of glucose and fat metabolism, as well as advanced skills in all aspects of study design, implementation, and evaluation and complete coursework in isotope tracers, biostatistics, and grant writing. The academic environment at Yale School of Medicine is rich in intellectual stimulation and houses ample resources critical to the completion of this proposal. Results obtained will reveal intricacies of metabolism in youth with T1D and become essential components of the NIDDK mission to “improve people's health and quality of life” by “disseminat[ing] science-based information on diabetes.” Furthermore, the results obtained will be critical in the preparation of my initial R01 application to evaluate the impact of adjunctive medications to decrease weight and insulin dose while improving glycemic control and outcomes in youth with obesity and T1D.