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 α ‐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 β ‐cells are emerging as central modulator(s) of α ‐cell biology. One of the most important of these paracrine factors, insulin, modulates glucagon secretion. Indeed, the α ‐cell‐specific insulin receptor knockout ( α IRKO) mouse manifests hypersecretion of glucagon in the postprandial stage and exhibits defective secretion in fasting‐induced hypoglycaemia, together mimicking the α ‐cell defects observed in type 2 diabetes. Interestingly, α IRKO mice display a progressive increase in β ‐cell mass and a concomitant decrease in α ‐cells. Lineage trace analyses reveal that the new β ‐cells originate, in part, from the insulin receptor‐deficient α ‐cells indicating a critical role for α ‐cell insulin signalling in determining β ‐cell origin. Our studies also reveal that glucagon‐like peptide‐1 (GLP‐1) treatment of α IRKO mice suppresses glucagon secretion despite absence of functional insulin receptors precluding a role for insulin in GLP‐1 action on α ‐cells in this model. These findings highlight the significance of insulin signalling in the regulation of α ‐cell biology.