title: Growth factor signalling in the regulation of α-cell fate.
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.
authors.affiliation: Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA. Rohit.Kulkarni@joslin.harvard.edu
authors.forename: D
authors.initials: D
authors.lastname: Kawamori
authors.forename: M
authors.initials: M
authors.lastname: Akiyama
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.forename: B
authors.initials: B
authors.lastname: Hambro
authors.forename: R N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D005934:Glucagon