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

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. (C) 2019 Elsevier Ltd. All rights reserved.