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β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response
- Source :
- Oncotarget, Paediatrics Publications
- Publication Year :
- 2016
- Publisher :
- Impact Journals LLC, 2016.
-
Abstract
- // 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 29
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....da7f70b99c1982942fae17d167eec766