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.
Highlights
The insulin receptor (IR) is a receptor tyrosine kinase with widespread expression that promotes glucose uptake to peripheral tissue in response to secreted insulin from the pancreatic β-cells [1]
Notable cellular functions regulated by autocrine/paracrine β-cell insulin signaling include insulin production and glucosestimulated insulin secretion [8]. β-cell IR signaling is required in vivo for adaptive islet hyperplasia in response to pancreatic injury and insulin resistance [9], and can www.impactjournals.com/oncotarget enhance rescue from a hyperglycemic state, as seen in diabetic rats transplanted with rat insulinoma (INS-1) cells overexpressing human IR [10]
We investigated the temporal role of β-cell IR knockout on the 2nd transition period of fetal β-cell development (Figure 1A), a crucial stage of pancreatic development characterized by endocrine cell proliferation and fate determination
Summary
The insulin receptor (IR) is a receptor tyrosine kinase with widespread expression that promotes glucose uptake to peripheral tissue in response to secreted insulin from the pancreatic β-cells [1]. We proposed to determine if β-cell IR is an essential regulator of β-cell development to reconcile conflicting findings from the aforementioned adult βIRKO [11] and fetal insulin [12] knockout studies, and investigate potential adaptive signaling from the homologous Igf-1r. Knockout of IR in β-cells was confirmed by western blot analyses and depicted a significant reduction in IR protein level (~75% lost) in MIP-βIRKO pancreata (p < 0.05 vs controls; Figure 1D).
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