Allen Root, MD

Global deficiency of IGF-I receptors result in hypoplasia of pancreatic islet β-cells.  In order to examine the role of the IGF-I receptor in an individual tissue, the investigators from the Joslin Clinic and elsewhere developed a mouse model in which there is "knock-out" of the IGF-I receptor on only the pancreatic islet β-cells.  All other tissues continue to express the IGF-I receptor normally, and circulating IGF-I concentrations are comparable to values in controls, indicating no generalized absence of IGF-I presence or action.  The investigators did so by breeding animals with conditional Igf1r targeting by a neomycin selection cassette for exon 3 flanked by loxP sites that was subsequently excised with mice expressing cre linked to the rat insulin promoter. 

β-cell–specific IGF-I receptor "knock-out" mice (KO) survived normally in utero and after birth.  β-cell mass, insulin, and glucagon content were normal in control and KO animals at 6 months.  In vitro, islets from KO mice failed to release insulin in response to glucose in a normal manner and basal insulin secretion was not suppressed by IGF-I added to the incubation medium.  In vivo, fasting glucose levels were similar, but basal insulin and C-peptide concentrations were higher in KO than in control mice.  There was impaired glucose tolerance following intraperitoneal glucose.  The immediate first phase of insulin secretion was absent, and the second phase was blunted in KO animals while the insulin secretory response to L-arginine was comparable in KO and control mice.  KO mice had reduced islet cell expression of the genes encoding important glucose-sensing proteins, including the GLUT-2 glucose transporter, and glucokinase which is the enzyme necessary for glucose phosphorylation.  Thus, the β-cell IGF-I receptor is not necessary for β-cell growth, but it is needed for the selective β-cell insulin secretory response to glucose.

Kulkarni RN, et al. β-cell-specific deletion of the IGF-I receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nature Genet 2002;31:111-115.

Editor’s Comment:  Present technology has opened the portal to the investigation of the function of cell-specific proteins.  One wonders if patients with impaired glucose tolerance, paradoxically increased basal insulin values, and subnormal insulin glucose-specific insulin secretion, present a loss-of-function defect in β-cell IGF-I receptors.  This article and the one on page 62 (β-Cell Expression) are related and have potential importance in the future treatment of diabetes mellitus.

Allen Root, MD