Glucose-Induced Cyclic-AMP Oscillations: Modeling Incretin Impact on Pancreatic Beta Cell Secretion

Abstract

Pancreatic beta cells modulate insulin secretion via incretin-induced amplification pathways of cytosolic calcium (Ca2+)-induced exocytosis, which may be help compensate for reduced insulin sensitivity in Type II Diabetes Mellitus. One modulator is cAMP, which is activated by an incretin-triggered Gs protein cascade and sensitive to glucose levels. Interestingly, cAMP is found to be oscillatory, even in cases where Ca2+ is not, providing a possible mechanism for pulstile insulin secretion in the absence of Ca2+ oscillations. When Ca2+ and cAMP both oscillate, the two may be either in-phase or out-of-phase with one another. To understand the cAMP oscillations and their relationship to Ca2+ oscillations we use mathematical modeling. We model the cAMP production sensitivity to glucose metabolism with AMP sensitive adenylyl cyclases and degradation with Ca2+ sensitive phosphodiesterases. These modest additions to the Dual Oscillator Model for beta cells allow us to capture observed relationships between cAMP and Ca2+. This provides further evidence for metabolic oscillations in beta-cells that are affected by, but that do not require, oscillations in Ca2+.