Effects of Intermittent Fasting on Glycemic Control in Patients with Diabetes

Intermittent fasting (IF) is an alternative to daily calorie restriction for producing clinically relevant weight loss. Though intermittent fasting does not increase weight loss relative to daily calorie restriction, modifying the timing of food intake via intermittent energy restriction (IER) or time-restricted eating (TRE), two forms of

intermittent fasting, may provide a pronounced benefit to glycemic control. However, these two IF approaches have not been thoroughly tested or compared in patients with type 2 diabetes (T2D). Further, pancreatic beta cell responsiveness and insulin action in response to a mixed meal depend on a functionally normal incretin

axis. Two insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are essential for postprandial glucose control. Incretin-stimulated insulin action contributes more than 70% of the insulin response to a meal in healthy adults, overshadowing the effect of glucose alone

to stimulate insulin secretion. In patients with type 2 diabetes, the incretin response is blunted, contributing to poorer glycemic control. Similarly, higher levels of inflammation blunt insulin sensitivity. Intermittent fasting reduces inflammation and improves incretin expression in mice, however these effects have yet to be

replicated in patients with T2D. Our goal is to evaluate potential mechanisms of benefit for two IF approaches on glycemic control in patients with T2D. The primary aim is to determine the effects of two forms of intermittent fasting on insulin action and whole-body insulin sensitivity. We will also compare changes in body

composition between IER and TRE and conduct the first trial to determine the effects of both intermittent fasting approaches on the incretin response to a meal. In exploratory analyses, we will phenotype individuals based on metabolic assessments to determine potential predictors of response from each intervention. We will

do this by leveraging and supplementing an existing randomized controlled trial utilizing both IF approaches within a 6-month multicomponent lifestyle change program incorporating a comprehensive health education program for diabetes via biweekly group meetings delivered remotely. Primary endpoints will be collected at

weeks 0, 12, and 26, and 52 weeks. In addition to data already being collected on weight change, glycemic control via HbA1c and continuous glucose monitoring, we will conduct a 3-hour, 9-point mixed meal tolerance test (MMTT) with glucose, insulin, and c-peptide to allow for estimates of insulin secretion and pancreatic beta

cell function. Additionally, we will assess the effects of IER and TRE on body composition, incretin response and inflammatory cytokine levels during the 12-month intervention. Mixed models with repeated measures analysis will be used to assess the effect of each approach on outcome measures and, secondarily, to

compare these two forms of IF. The long-term goal of our research is to determine whether intermittent fasting approaches are an effective alternative to standard of care for diabetes treatment. Secondarily, our goal is to determine which patients are most likely to benefit from either intermittent fasting regimen.