Beta-cell ARNT is required for normal glucose tolerance in murine pregnancy
AIMS: Insulin secretion increases in normal pregnancy to meet increasing demands. Inability to increase beta-cell function results in gestational diabetes mellitus (GDM). We have previously shown that the expression of the transcription factor ARNT (Aryl-hydrocarbon Receptor Nuclear Translocator) is reduced in the islets of humans with type 2 diabetes. Mice with a beta-cell specific deletion of ARNT (beta-ARNT mice) have impaired glucose tolerance secondary to defective insulin secretion. We hypothesised that ARNT is required to increase beta-cell function during pregnancy, and that beta-ARNT mice would be unable to compensate for the beta-cell stress of pregnancy. The aims of this study were to investigate the mechanisms of ARNT regulation of beta-cell function and glucose tolerance in pregnancy. METHODS: beta-ARNT females were mated with floxed control (FC) males and FC females with beta-ARNT males. RESULTS: During pregnancy, beta-ARNT mice had a marked deterioration in glucose tolerance secondary to defective insulin secretion. There was impaired beta-cell proliferation in late pregnancy, associated with decreased protein and mRNA levels of the islet cell-cycle regulator cyclinD2. There was also reduced expression of Irs2 and G6PI. In contrast, in control mice, pregnancy was associated with a 2.1-fold increase in ARNT protein and a 1.6-fold increase in cyclinD2 protein, and with increased beta-cell proliferation. CONCLUSIONS: Islet ARNT increases in normal murine pregnancy and beta-cell ARNT is required for cyclinD2 induction and increased beta-cell proliferation in pregnancy.
|Authors||Lau, S. M.; Cha, K. M.; Karunatillake, A.; Stokes, R. A.; Cheng, K.; McLean, M.; Cheung, N. W.; Gonzalez, F. J.; Gunton, J. E.;|
|Responsible Garvan Author|
|Publisher Name||PLoS One|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24204824|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11868|