Mathematical modeling informs the impact of changes in circadian rhythms and meal patterns on insulin secretion

Abstract

Disruption of circadian rhythms has been associated with metabolic syndromes, including obesity and diabetes. A variety of metabolic activities are under circadian modulation, as local and global clock gene knockouts result in glucose imbalance and increased risk of metabolic diseases. Insulin release from the pancreatic β cells exhibits daily variation, and recent studies have found that insulin secretion, not production, is under circadian modulation. As consideration of daily variation in insulin secretion is necessary to accurately describe glucose-stimulated insulin secretion, we describe a mathematical model that incorporates the circadian modulation via insulin granule trafficking. We use this model to understand the effect of oscillatory characteristics on insulin secretion at different times of the day. Furthermore, we integrate the dynamics of clock genes under the influence of competing environmental signals (light/dark cycle and feeding/fasting cycle) and demonstrate how circadian disruption and meal size distribution change the insulin secretion pattern over a 24-h day.