PROJECT SUMMARY/ABSTRACT Thirty years of follow up data from two landmark trials (DCCT/EDIC) demonstrates that intensive insulin management to achieve near-normal blood glucose levels decreases the risk of retinopathy, neuropathy, and nephropathy for individuals with type 1 diabetes (T1D).1,2 Yet, achieving near-normal blood glucose levels increases the risk of severe hypoglycemia in those with T1D by 3-fold. Currently, there are no specific dietary recommendations from the American Diabetes Association for pediatric T1D;3 however, a growing number of youth with T1D and their parents are interested in very low carbohydrate diets to improve blood glucose control.4 There has been hesitance to prescribe such diets to adolescents as no rigorous studies have been performed in this age group. The goal of this proposal is to determine the safety and efficacy of a very low carbohydrate diet in adolescents with T1D by looking at metabolic and neurological changes that occur with this diet. Aim 1 of this proposal uses a randomized crossover study design to compare the time spent in the target range using continuous glucose monitors when adolescents with T1D follow a standard versus very low carbohydrate diet. Less time in the hyperglycemic and hypoglycemic ranges indicates better safety. The number of episodes of diabetic ketoacidosis and severe hypoglycemia will also be reported. Aim 2 will compare the counterregulatory hormone response to hypoglycemia between the 2 diets using the 2-step hyperinsulinemic euglycemic-hypoglycemic clamp technique. Stable isotope infusions will be used to assess rates of hepatic glucose production (glucose release from the liver) and glycerol metabolism from adipose tissue. Further, very low carbohydrate diets are likely to cause higher ketone levels in the blood (nutritional ketosis), but there is little known about how this will affect awareness of hypoglycemia and other neurological changes. Aim 3 will assess changes in symptoms of hypoglycemia using validated questionnaires during the hypoglycemia portion of the clamp, which will be correlated with fMRI findings. Through this aim, we will determine if the ketosis that develops in very low carbohydrate diets will blunt warning signs of hypoglycemia. Dr. Nally has assembled a leadership team with a diverse skillset to guide her in this research. Dr. Nally's primary mentor, Dr. William Tamborlane, has over 45 years of experience in pediatric T1D research and has mentored 14 current physician scientist faculty at Yale. Dr. Raimund Herzog (co-mentor) has expertise in the metabolic effects of hypoglycemia and ketosis on the brain and will guide Dr. Nally with these aspects of the study. With expertise in pediatric T1D, continuous glucose monitoring and the hyperinsulinemic euglycemic- hypoglycemic clamps, Dr. Jennifer Sherr (co-mentor) will ensure Dr. Nally has the skillset necessary to conduct the studies proposed herein. Dr. Nally will gain expertise in sophisticated measur...