20.500.12556/DKUM-89006 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 ATPdependent closure of KATP 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. pancreatic alpha cell glucagon cAMP mathematical model diabetes cellular bioenergetics true true true MDPI Angleški jezik Angleški jezik Članek v reviji 2024-06-05 03:25:10 2024-06-06 08:33:59 2024-06-07 03:17:47 0000-00-00 00:00:00 2021 0 0 22 str. iss. 4 Vol. 10 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2021-03-15 2021-04-12 2021-04-14 612.349.7 59694339 10.3390/cells10040896 2073-4409 https://www.mdpi.com/2073-4409/10/4/896 1 74486026-22da-11ef-9e9b-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=180203 RAZ_Zmazek_Jan_2021.pdf RAZ_Zmazek_Jan_2021.pdf 1 CA82892AE60A59840969139C04569A1B d0ac61f0922b93a11275abeace233d92357557187a5392f35dedc3b78ce33d1a d51761df-23d0-11ef-9cfe-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=180250 Fakulteta za naravoslovje in matematiko Fakulteta za elektrotehniko, računalništvo in informatiko Pedagoška fakulteta Medicinska fakulteta 0 0 0