Growth factor signalling in the regulation of α-cell fate

Glucagon plays critical roles in regulating glucose homeostasis, mainly by counteracting the effects of insulin. Consequently, the dysregulated glucagon secretion that is evident in type 2 diabetes has significant implications in the pathophysiology of the disease. Glucagon secretion from pancreatic alpha-cells has been suggested to be modulated by blood glucose, signals from the nervous system and endocrine components. In addition to these regulators, intraislet factors acting in a paracrine manner from neighbouring beta-cells are emerging as central modulator(s) of alpha-cell biology. One of the most important of these paracrine factors, insulin, modulates glucagon secretion. Indeed, the alpha-cell-specific insulin receptor knockout (alpha IRKO) mouse manifests hypersecretion of glucagon in the postprandial stage and exhibits defective secretion in fasting-induced hypoglycaemia, together mimicking the alpha-cell defects observed in type 2 diabetes. Interestingly, alpha IRK0 mice display a progressive increase in beta-cell mass and a concomitant decrease in alpha-cells. Lineage trace analyses reveal that the new beta-cells originate, in part, from the insulin receptor-deficient alpha-cells indicating a critical role for alpha-cell insulin signalling in determining beta-cell origin. Our studies also reveal that glucagon-like peptide-1 (GLP-1) treatment of alpha IRK mice suppresses glucagon secretion despite absence of functional insulin receptors precluding a role for insulin in GLP-1 action on alpha-cells in this model. These findings highlight the significance of insulin signalling in the regulation of alpha-cell biology.