Role of cAMP in Double Switch of Glucagon Secretion

Glucose metabolism plays a crucial role in modulating glucagon secretion in pancreatic alpha cells. However, the downstream effects of glucose metabolism and the activated signaling pathways influencing glucagon granule exocytosis are still obscure. We developed a computational alpha cell model, implementing metabolic pathways of glucose and free fatty acids (FFA) catabolism and an intrinsically activated cAMP signaling pathway. According to the model predictions, increased catabolic activity is able to suppress the cAMP signaling pathway, reducing exocytosis in a Ca2+-dependent and Ca2+ independent manner. The effect is synergistic to the pathway involving ATP-dependent closure of K-ATP channels and consequent reduction of Ca2+. We analyze the contribution of each pathway to glucagon secretion and show that both play decisive roles, providing a kind of secure double switch. The cAMP-driven signaling switch plays a dominant role, while the ATP-driven metabolic switch is less favored. The ratio is approximately 60:40, according to the most recent experimental evidence.

Automated summary

The computational alpha cell model showed that increased catabolic activity can suppress the cAMP signaling pathway, thereby reducing glucagon granule exocytosis. It was also found that both cAMP-driven signaling switch and ATP-driven metabolic switch play decisive roles in glucagon secretion, with a ratio of approximately 60:40 favoring the former according to recent experimental evidence.