Epidermal Growth Factor Signalling Promotes Pancreatic Beta-Cell Proliferation in Response to Nutrient Excess in Rats Through MTOR And FOXM1

Abstract

A compensatory increase in beta-cell mass occurs in several physiological and pathophysiological situations, such as pregnancy, obesity and insulin resistance. We have previously observed that a 72-hour co-infusion of glucose and Intralipid (GLU+IL) in 6-month-old (6-mo) rats causes insulin resistance and beta-cell dysfunction, despite a marked increase in beta-cell proliferation and mass. Interestingly, none of these effects were observed in 2-month-old (2-mo) animals despite similar levels of circulating glucose, fatty acids and insulin. Islet gene expression profiling in 6-mo GLU+IL rats identified a transcriptional network associated with beta-cell proliferation and a central role for the forkhead transcription factor FoxM1. Expression of the heparin binding EGF-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), was significantly induced in response to GLU+IL. First, we confirmed by RT-PCR the increased expression of HB-EGF, FoxM1 and its direct targets in islets from GLU+IL-infused 6-mo, but not 2-mo rats. Second, we observed that the expression of HB-EGF correlates significantly and positively with the expression of FoxM1 and its direct targets. Third, co-infusion of either the EGFR inhibitor, AG1478 or the mTOR inhibitor, rapamycin, blocked the increase in expression of FoxM1 and its targets in response to GLU+IL in 6-mo rats. Finally, HB-EGF induces the proliferation of insulin-secreting MIN6 cells, and this effect was blocked by AG1478 or rapamycin. We conclude that insulin resistance induced by nutrient excess in aging rats promotes beta-cell proliferation via a pathway that involved HB-EGF binding to EGFR, mTOR activation and FoxM1-mediated cell division.