β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response
Autor: | Amanda Oakie, Matthew Riopel, Liangyi Zhou, Mark Trinder, Rennian Wang |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
medicine.medical_specialty islet vasculature medicine.medical_treatment Inducible MIP-βIRKO 03 medical and health sciences Paracrine signalling Islets of Langerhans Mice inducible MIP-βIRKO Pregnancy Internal medicine Insulin-Secreting Cells β-cell proliferation Pathology Section medicine Animals fetal pancreas Autocrine signalling Protein kinase B Mice Knockout geography Fetus geography.geographical_feature_category Fetal pancreas biology business.industry Insulin Islet vasculature Islet Research Paper: Pathology Receptor Insulin 3. Good health Insulin receptor 030104 developmental biology Endocrinology medicine.anatomical_structure Oncology biology.protein Female Pancreas business |
Zdroj: | Oncotarget Paediatrics Publications |
ISSN: | 1949-2553 |
Popis: | // Mark Trinder 1,2,* , Liangyi Zhou 1,3,* , Amanda Oakie 1,3 , Matthew Riopel 1 and Rennian Wang 1,2,4 1 Children’s Health Research Institute, London, Ontario, Canada 2 Departments of Physiology & Pharmacology, University of Western Ontario, London, Ontario, Canada 3 Department of Pathology, University of Western Ontario, London, Ontario, Canada 4 Department of Medicine, University of Western Ontario, London, Ontario, Canada * These authors have contributed equally to this study Correspondence to: Rennian Wang, email: // Keywords : inducible MIP-βIRKO, fetal pancreas, β-cell proliferation, islet vasculature, Pathology Section Received : October 28, 2015 Accepted : June 12, 2016 Published : June 30, 2016 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 2 nd 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. |
Databáze: | OpenAIRE |
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