Oncotarget

Research Papers: Pathology:

β-cell insulin receptor deficiency during in utero development induces an islet compensatory overgrowth response

Mark Trinder _, Liangyi Zhou, Amanda Oakie, Matthew Riopel and Rennian Wang

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Oncotarget. 2016; 7:44927-44940. https://doi.org/10.18632/oncotarget.10342

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Abstract

Mark Trinder1,2,*, Liangyi Zhou1,3,*, Amanda Oakie1,3, Matthew Riopel1 and Rennian Wang1,2,4

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 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.


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