Growth factor signalling in the regulation of α-cell fate

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2011-10, Vol.13 (s1), p.21-30
• Main Authors: Kawamori, D., Akiyama, M., Hu, J., Hambro, B., Kulkarni, R. N.
• Format: Article
• Language: English
• Subjects: Animals; Beta cells; Blood Glucose - genetics; Blood Glucose - metabolism; Cell fate; cell growth; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Gene Expression Regulation; GLP-1; Glucagon; Glucagon - genetics; Glucagon - metabolism; Glucagon - secretion; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide 1 - metabolism; Glucagon-Secreting Cells - metabolism; Homeostasis; Humans; Hypoglycemia; Insulin; Insulin receptors; insulin signalling; Mice; Mice, Knockout; Nervous system; Paracrine signalling; Secretion; Signal Transduction
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2011.01442.x

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 (αIRKO) 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, αIRKO 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 αIRKO 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.