The scientific goal of this application is to explore the mechanisms linking diet to metabolism and body weight control, with relevance to type one diabetes mellitus (T1D). The career development goal is to advance my training in neuroimaging, nutrition, and clinical trial conduct - in preparation for my transition to independence. Despite major technological advances, management of T1D remains suboptimal, putting millions of people at risk for immediate and long-term complications. Moreover, individuals with T1D have elevated rates of dysregulated eating, overweight, and metabolic syndrome, further contributing to chronic disease risk. In this proposal, I consider control of the postprandial state as mechanistically related to each of these pathophysiological challenges. After meals, a mismatch between carbohydrate absorption rate and insulin action typically leads to alternating periods of hyper- and hypoglycemia, compounded by potential adverse effects of higher systemic insulin exposure (e.g. anabolic effects, insulin resistance). A conceptually promising approach to control both problems is dietary carbohydrate modification to reduce postprandial glycemia and insulin needs. In prior work, I demonstrated that high- vs low- glycemic index (GI) carbohydrate increased hunger and activation of brain areas involved in addiction and craving in individuals without diabetes. A survey study documented exceptional glycemic control (HbA1c 5.7% and low acute complication rate) among 316 children and adults with T1D consuming a very-low-carbohydrate diet (VLCD). Here I propose two complementary studies: (1) Leveraging neuroimaging and metabolic data obtained from a controlled, cross-over feeding protocol involving intravenous insulin administration, I will explore whether the effects of high GI carbohydrates on hunger, metabolic outcomes, and brain function are mediated by mechanisms related to blood glucose, serum insulin or both. (2) In a 12-week randomized trial, I will assess the safety and preliminary efficacy of a VLCD in the management of adolescents and young adults with T1D. As a result of these studies, I hope to help elucidate mechanisms relating type and amount of dietary carbohydrate to glycemia, brain control of body weight and cardio metabolic risk in T1D, and provide data of direct relevance to the clinical management.
Type one diabetes (T1D) management presents major challenges to children and adults alike, including short and long-term complications from blood glucose fluctuation and adverse metabolic effects from chronic systemic (versus hepatic) hyperinsulinemia. This proposal will explore physiological mechanisms linking dietary carbohydrate to hunger, metabolic outcomes, and brain control of body weight, and assess the safety and preliminary efficacy of a very low carbohydrate diet for adolescents and young adults with T1D. A successful outcome of this project will contributed to scientific understanding, test a promising new treatment for T1D, and provide Dr. Lennerz a training opportunity to transition into professional independence as an academic physician- scientist.
