Mechanisms of Beta Cell Metabolic Coordination

Abstract

Glucose homeostasis is predominantly regulated by pancreatic hormones. Insulin, which is secreted by pancreatic beta cells, is vital for maintaining normoglycemia; insulin secretory failure is a prime contributor to diabetes progression. The insulin secreting beta cells are a heterogeneous population that are organized into islets, which display coordinated responses to glucose. Although the electrical coupling of beta cells is well described, upstream metabolic coupling has not been sufficiently explored. The goal of this research was to (1) determine if beta cells are metabolically coordinated prior to reaching electrical threshold potential, (2) confirm evidence of metabolic heterogeneity, and (3) examine the importance of this heterogeneity. To accomplish this goal, we used a variety of novel techniques and models. We restricted application of glucose to portions of the islet to show beta cells are metabolically coordinated by gap junctional diffusion of metabolites. Then, using mice expressing a plasma membrane ChR2, we demonstrated that beta cell metabolism is differentially regulated by calcium. Finally, we generated a novel mouse model expressing an anisotropic reporter of glucokinase activity to illustrate that differences in glucokinase activity are averaged by metabolic coupling. These results highlight the importance of metabolic coordination in evening out differences between cells. Our findings may explain how insulin secretion is enhanced in the presence of glucose but contained in its absence.