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

ABSTRACT

The presence of insulin receptor (IR) on ß-cells suggests that insulin has an autocrine/paracrine role in the regulation of ß-cell function. It has previously been reported that the ß-cell specific loss of IR (ßIRKO) leads to the development of impaired glycemic regulation and ß-cell death in mice. However, temporally controlled ßIRKO induced during the distinct transitions of fetal pancreas development has yet to be investigated. We hypothesized that the presence of IR on ß-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-ßIRKO) mouse model to investigate the loss of ß-cell IR during pancreatic development at embryonic day (e) 13, a phase of endocrine proliferation and ß-cell fate determination. Fetal pancreata examined at e19-20 showed significantly reduced IR levels in the ß-cells of MIP-ßIRKO mice. Morphologically, MIP-ßIRKO pancreata exhibited significantly enlarged islet size with increased ß-cell area and proliferation. MIP-ßIRKO 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-ßIRKO pancreata.Our results demonstrate a developmental role for the ß-cell IR, whereby its loss leads to an islet compensatory overgrowth, and contributes further information towards elucidating the temporally sensitive signaling during ß-cell commitment.