Heterogeneous alpha-cell population modeling of glucose-induced inhibition of electrical activity

•Control of glucagon secretion from alpha-cells due to glucose is still unclear•We implement alpha-cell population model with realistic heterogeneity•The model reproduces various electrophysiological responses to rise in glucose levels•At population level, we achieve reduced electrical activity due to glucose increase•Statistical analyses clarify the role of different types of ion channels Glucagon release from the pancreatic alpha-cells is regulated by glucose, but the underlying mechanisms are far from understood. It is known that the alpha-cell population is very heterogeneous, but – compared to the insulin-secreting beta-cells – the consequences of this cell-to-cell variation are much less studied. Since the alpha-cells are not electrically coupled, large differences in the single cell responses are to be expected, and this variation may contribute to the confusion regarding the mechanisms of glucose-induced suppression of glucagon release. Using mathematical modeling of alpha-cells with realistic cell-to-cell parameter variation based on recent experimental results, we show that the simulated alpha-cells exhibit great diversity in their electrophysiological behavior. To robustly reproduce experimental recordings from alpha-cell exposed to a rise in glucose levels, we must assume that both intrinsic mechanisms and paracrine signals contribute to glucose-induced changes in electrical activity. Our simulations suggest that the sum of different electrophysiological responses due to alpha-cell heterogeneity is involved in glucose-suppressed glucagon secretion, and that more than one mechanism contribute to control the alpha-cell populations’ behavior. Finally, we apply regression analysis to our synthetic alpha-cell population to infer which membrane currents influence electrical activity in alpha-cells at different glucose levels. The results from such statistical modeling suggest possible disturbances underlying defect regulation of alpha-cell electrical behavior in diabetics. Thus, although alpha-cells appear to be inherently complex and heterogeneous as reflected in published data, realistic modeling of the alpha-cells at the population level provides insight into the mechanisms of glucagon release.