Alpha-cell glucagon is essential for maintaining β-cell function and identity in adult mice.

Several studies have analyzed the effect of glucagon on β-cells and glucose homeostasis, either by ablating α-cells or by globally deleting the glucagon/glucagon receptor gene. To investigate possible interactions between α-cells and β-cells, and the effect of α-cells on β-cells/glucose homeostasis, we generated mouse models to allow deletion of the glucagon gene in α-cells (acute-α-GCG-KO) and the glucagon receptor gene in β-cells of adult mice. Specific deletion of the glucagon gene in the α-cell in adult mice led to impaired glucose tolerance, reduced β-cell mass and function, islet inflammation, β-cell endoplasmic reticulum stress, and altered β-cell ultrastructure. Notably, these detrimental effects were reversed by exogenous glucagon administration, but not by the glucagon-like peptide-1 analog exendin-4, indicating that glucagon deficiency specifically harms β-cells. Interestingly, acute ablation of α-cells in acute-α-GCG-KO mice reversed the alteration in glucose homeostasis and in β cells, suggesting that α-cells lacking glucagon gene expression can negatively impact β-cells, perhaps by some unknown factor(s). To investigate the role of the β-cell's glucagon receptor on the observed effect of glucagon gene deletion, we specifically deleted the glucagon receptor gene in β-cells, either congenitally or acutely in the adult mouse; here, there were no changes in β-cells and glucose homeostasis, suggesting that the effect of glucagon on β-cells can be mediated via other signaling pathways. Conclusion: Glucagon gene deletion in α-cells of adult mice is detrimental to β-cells, and this effect is reversed by glucagon administration, suggesting that glucagon deficiency is specifically injurious to β-cells.