General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.6

Aims/hypothesis The stress-activated nuclear protein transcription regulator 1 (NUPR1) is induced in response to glucose and TNF-α, both of which are elevated in type 2 diabetes, and Nupr1 has been implicated in cell proliferation and apoptosis cascades. We used Nupr1 −/− mice to study the role of Nupr1 in glucose homeostasis under normal conditions and following maintenance on a high-fat diet (HFD). Methods Glucose homeostasis in vivo was determined by measuring glucose tolerance, insulin sensitivity and insulin secretion. Islet number, morphology and beta cell area were assessed by immunofluorescence and morphometric analysis, and islet cell proliferation was quantified by analysis of BrdU incorporation. Islet gene expression was measured by gene arrays and quantitative RT-PCR, and gene promoter activities were monitored by measuring luciferase activity. Results Nupr1 −/− mice had increased beta cell mass as a consequence of enhanced islet cell proliferation. Nupr1-dependent suppression of beta cell Ccna2 and Tcf19 promoter activities was identified as a mechanism through which Nupr1 may regulate beta cell cycle progression. Nupr1 −/− mice maintained on a normal diet were mildly insulin resistant, but were normoglycaemic with normal glucose tolerance because of compensatory increases in basal and glucose-induced insulin secretion. Nupr1 deletion was protective against HFD-induced obesity, insulin resistance and glucose intolerance. Conclusions/interpretation Inhibition of NUPR1 expression or activity has the potential to protect against the metabolic defects associated with obesity and type 2 diabetes.

It is well established that the maternal β-cell mass increases during pregnancy in both humans and rodents to compensate insulin resistance and increased metabolic demand, and rapidly returns to normal levels post-partum. However, the mechanisms underlying this adaptation are not well understood. It is established that this process is driven partly by placental signals, but the contribution of non-placental signals is still unclear. This study aimed to differentiate between the role of placental and non-placental signals in regulating the β-cell mass and glucose homeostasis during and after pregnancy. Pseudopregnant, pregnant and lactating mice were used to study the effects of maternal hormones on β-cell function during early pregnancy, mid-to-late pregnancy and post-partum, respectively. Pseudopregnant mice, with circulating hormone levels mirroring those during pregnancy but lacking placental signals, had significantly increased β-cell proliferation compared to non-pregnant controls but no change in glucose homeostasis, suggesting a role for non-placental hormones in increasing β-cell mass. The rate of β-cell proliferation rate dropped immediately after parturition, but lactating mice still had a significantly higher rate of β-cell proliferation compared to non-lactating post-partum mice, suggesting that lactation-related hormones play a role in the controlled involution of β-cell mass post-partum. These results implicate a role for both non-placental and placental signals in regulating β-cell mass during and after pregnancy.

We recently reported that deletion of the stress-regulated nuclear protein 1 (Nupr1) protected against obesity-associated metabolic alterations due to increased beta cell mass, but complete Nupr1 ablation was not advantageous since it led to insulin resistance on a normal diet. The current study used Nupr1 haplodeficient mice to investigate whether a partial reduction in Nupr1 expression conferred beneficial effects on glucose homeostasis. Islet number, morphology and area, assessed by immunofluorescence and morphometric analyses, were not altered in Nupr1 haplodeficient mice under normal diet conditions and nor was beta cell BrdU incorporation. Glucose and insulin tolerance tests indicated that there were no significant changes in in vivo insulin secretion and glucose clearance in Nupr1 haplodeficient mice, and beta cell function in vitro was normal. However, reduced Nupr1 expression decreased visceral fat deposition and significantly increased insulin sensitivity in vivo. In contrast to wild type animals, high fat diet-fed Nupr1 haplodeficient mice were not hyperinsulinaemic or glucose intolerant, and their sustained insulin sensitivity was demonstrated by appropriate insulin-induced Akt phosphorylation, as determined by Western blotting. At the molecular level, measurements of gene expression levels and promoter activities identified Nupr1-dependent inhibition of heat shock factor-1-induced heat shock protein 70 (Hsp70) expression as a mechanism through which Nupr1 regulates insulin sensitivity. We have shown for the first time that Nupr1 plays a central role in inhibiting Hsp70 expression in tissues regulating glucose homeostasis, and reductions in Nupr1 expression could be used to protect against the metabolic defects associated with obesity-induced insulin resistance.

Background/Aims: Insulin-secreting islet β-cells adapt to the insulin resistance associated with pregnancy by increasing functional β-cell mass, but the placental signals involved in this process are not well defined. In the current study, we analysed expression of G-protein coupled receptor (GPCR) mRNAs in mouse islets and islet GPCR ligand mRNAs in placenta during pregnancy to generate an atlas of potential interactions between the placenta and β-cells to inform future functional studies of islet adaptive responses to pregnancy. Methods: Quantative RT-PCR arrays were used to measure mRNA expression levels of: (i) 342 GPCRs in islets from non-pregnant mice, and in islets isolated from mice on gestational days 12 and 18; (ii) 126 islet GPCR ligands in mouse placenta at gestational days 12 and 18. Results: At gestational day 12, a time of rapid expansion of the β-cell mass, 189 islet GPCR mRNAs were quantifiable, while 79 of the 126 known islet GPCR ligand mRNAs were detectable in placental extracts. Approximately half of the quantifiable placental GPCR ligand genes were of unknown function in β-cells. The expression of some islet GPCR and placental ligand mRNAs varied during pregnancy, with altered expression of both GPCR and ligand mRNAs by gestational day 18. Conclusion: The current study has revealed numerous potential routes for interaction between the placenta and islets, and offers an atlas to inform further functional studies of their roles in adaptive responses to pregnancy, and in the regulation of the β-cell mass.