Abstract
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 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.
Highlights
Type 2 diabetes mellitus (T2DM) represents a significant public health problem, with more than 7% of the adult population being affected [1]
We model the mechanisms involved in the modulation of soluble adenylyl cyclases (sACs) activity and consequent cAMP production. cAMP is a ubiquitous second messenger, the activator of effector proteins involved in proliferation, differentiation, secretion, contractility etc. [49]. cAMP effector proteins involve protein kinase A (PKA), exchange factor directly activated by cyclic AMP (EPAC), cyclic AMP responsive ion channels (CICs), and the Popeye domaincontaining (POPDC) proteins
The here introduced double switch for glucagon secretion illustrates a synergistic action of two important mechanisms
Summary
Type 2 diabetes mellitus (T2DM) represents a significant public health problem, with more than 7% of the adult population being affected [1]. Since glucose increase does not significantly reduce Ca2+ under hyperglycemia [8], other factors probably regulate glucagon exocytosis in alpha cells apart from depolarization-induced inactivation voltage-dependent calcium channels (VDCC). Such factors may include AMPactivated protein kinase (AMPK) signaling [9], cAMP-PKA/Epac [10], and other signaling pathways [11]. In addition to cAMP signaling, alpha cells possess another mechanism for regulating glucose-induced glucagon secretion, operating on the basis of the metabolism-induced increase in ATP concentration. The results are discussed in the context of the most recent experimental data [23]
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