PROJECT SUMMARY Type 1 diabetes (T1D) is caused by autoimmune destruction of β-cells that causes dependence on exogenous insulin. Despite remarkable advances in diabetes device technology, less than 25% of adults with T1D achieve the recommended HbA1c target of <7.0%. Moreover, subcutaneous delivery of insulin eliminates the normal portal-to-peripheral insulin gradient and causes “iatrogenic hyperinsulinemia” and whole-body insulin resistance, which increases the risk of cardiovascular complications. Novel therapies that improve glycemic control and reduce insulin requirements are needed to improve outcomes in people with T1D. A very-low-carbohydrate ketogenic diet (≤50 g carbohydrate/day) could reduce glycemic variability, total daily insulin requirement, and HbA1c in people with T1D. Indeed, several case series and observational studies of using a ketogenic diet (KD) in people with T1D have observed such benefits. However, we are not aware of any randomized controlled trials (RCTs) that evaluated the efficacy of KD for >7 days in people with T1D. In addition, there are serious concerns regarding the safety and tolerability of a KD in patients with T1D, including the potential for an increased risk of hypoglycemia, diabetic ketoacidosis, dyslipidemia, insulin resistance, decreased bone mineral density, and impaired quality of life. The purpose of this proposal is to conduct a two-site (Washington University School of Medicine in St. Louis, MO and Sansum Diabetes Research Institute in Santa Barbara, CA) 26-week RCT to evaluate the clinical efficacy, metabolic function, safety, socio-behavioral impact, acceptability and potential for dissemination of an isocaloric KD compared with an American Diabetes Association-recommended control diet in 80 adults with T1D. The following specific aims will be addressed: 1) determine the clinical efficacy and cardiometabolic effects of KD therapy in patients with T1D, including glycemic control [percent time-in-range 70-180 mg/dL (primary outcome), percent time in 70-140 mg/dL, mean glucose, glucose variability, and HbA1c], insulin sensitivity (determined by the hyperinsulinemic-euglycemic clamp procedure) (primary outcome), daily insulin requirement, 24-hour serial plasma glucose, FFA, triglyceride, insulin, glucagon, and ketone body concentrations; plasma lipid profile, hepatic de novo lipogenesis and cholesterol synthesis, body composition (fat-free mass, fat mass, appendicular lean mass, intra-abdominal adipose tissue, and intrahepatic triglyceride content), and selected plasma markers of inflammation; 2) assess the safety of KD therapy with respect to hypoglycemia, hyperketonemia, renal function and bone health; and 3) assess socio-behavioral factors and implementation outcomes, including sociodemographic factors (social determinants, unmet social needs), behavioral factors (eating behaviors, food cravings, diabetes distress and quality-of-life); and implementation outcomes (acceptability, feasibility, p...