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Diabetes Obes Metab. 2011 Oct;13 Suppl 1:21-30. doi: 10.1111/j.1463-1326.2011.01442.x.

Growth factor signalling in the regulation of α-cell fate.

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1
Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA. Rohit.Kulkarni@joslin.harvard.edu

Abstract

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.

[Indexed for MEDLINE]

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