title: β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response.
abstract: The presence of insulin receptor (IR) on β-cells suggests that insulin has an autocrine/paracrine role in the regulation of β-cell function. It has previously been reported that the β-cell specific loss of IR (βIRKO) leads to the development of impaired glycemic regulation and β-cell death in mice. However, temporally controlled βIRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on β-cells during the 2nd transition phase of the fetal murine pancreas is required for maintaining normal islet development.We utilized a mouse insulin 1 promoter driven tamoxifen-inducible Cre-recombinase IR knockout (MIP-βIRKO) mouse model to investigate the loss of β-cell IR during pancreatic development at embryonic day (e) 13, a phase of endocrine proliferation and β-cell fate determination. Fetal pancreata examined at e19-20 showed significantly reduced IR levels in the β-cells of MIP-βIRKO mice. Morphologically, MIP-βIRKO pancreata exhibited significantly enlarged islet size with increased β-cell area and proliferation. MIP-βIRKO pancreata also displayed significantly increased Igf-2 protein level and Akt activity with a reduction in phospho-p53 when compared to control littermates. Islet vascular formation and Vegf-a protein level was significantly increased in MIP-βIRKO pancreata.Our results demonstrate a developmental role for the β-cell IR, whereby its loss leads to an islet compensatory overgrowth, and contributes further information towards elucidating the temporally sensitive signaling during β-cell commitment.
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada.|Departments of Physiology & Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Trinder
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada.|Department of Pathology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Liangyi
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada.|Department of Pathology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oakie
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Riopel
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada.|Departments of Physiology & Pharmacology, University of Western Ontario, London, Ontario, Canada.|Department of Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Rennian
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D005260:Female; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011972:Receptor, Insulin / Q000172:deficiency*
chemical_list: D011972:Receptor, Insulin
keywords: Pathology Section; fetal pancreas; inducible MIP-βIRKO; islet vasculature; β-cell proliferation