Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3)

Abstract

Aims/hypothesis Human patients with aniridia caused by heterozygous PAX6 mutations display abnormal glucose metabolism, but the underlying molecular mechanism is largely unknown. Disturbed islet architecture has been proposed as the reason why mice with complete inactivation of paired box 6 (PAX6) in the pancreas develop diabetes. This is not, however, the case in human aniridia patients with heterozygous PAX6 deficiency and no apparent defects in pancreatic development. We investigated the molecular mechanism underlying the development of abnormal glucose metabolism in these patients. Methods A human aniridia pedigree with a PAX6 R240Stop mutation was examined for abnormal glucose metabolism using an OGTT. The underlying mechanism was further investigated using Pax6 R266Stop mutant small-eye mice, which also have abnormal glucose metabolism similar to that in PAX6 R240Stop mutation human aniridia patients. Results Paired box 6 (PAX6) deficiency, both in aniridia patients with a heterozygous PAX6 R240Stop mutation and in mice with a heterozygous Pax6 R266Stop mutation, causes defective proinsulin processing and abnormal glucose metabolism. PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin. Pax6 mutations lead to PC1/3 deficiency, resulting in defective proinsulin processing and abnormal glucose metabolism. Conclusions/interpretation This study indicates a novel function for PAX6 in the regulation of proinsulin processing and glucose metabolism via modulation of PC1/3 Diabetologia

A common variant upstream of the PAX6 gene influences islet function in man

“…The similarity of effects in vivo and in vitro in human islets provides strong support for the central role of PAX6 in development of islet function and regulation of glucose metabolism. The finding that low PAX6 expression causes impaired insulin secretion and affects glucose metabolism is in line with previously published findings in both animal models and human families with protein-altering mutations in the PAX6 gene [4][5][6][7]. However, these studies were performed in individuals with more severe mutations making generalisation of the findings to potential effects of common variants in the gene difficult.…”

“…Impaired proinsulin processing was expected in risk allele carriers based upon the concomitant decrease in expression of genes encoding the proinsulin processing enzymes PCSK1 and PCSK2. This was also the case in the family study by Wen et al where an elevated proinsulin/insulin ratio was associated with a decreased expression of PCSK1 [6]. In contrast, in the present study risk allele carriers showed a decreased proinsulin/insulin ratio despite lower mRNA levels of both PCSK1 and PCSK2.…”

“…There have been several reports of PAX6 mutation carriers having abnormal glucose tolerance, and of type 2 diabetes co-segregating with aniridia in families with PAX6 mutations [4][5][6]. Recently, Wen et al reported that carriers of a PAX6 R240Stop mutation developed impaired glucose tolerance and/or diabetes with age [6]. Mutation carriers had an increased proinsulin/insulin ratio and reduced insulin response to an OGTT [6].…”

“…Recently, Wen et al reported that carriers of a PAX6 R240Stop mutation developed impaired glucose tolerance and/or diabetes with age [6]. Mutation carriers had an increased proinsulin/insulin ratio and reduced insulin response to an OGTT [6]. By generating mice with a corresponding stop-mutation, the authors could demonstrate that PAX6 deficiency reduced the production of prohormone convertase (PC)1/3 and that the PCSK1 gene encoding PC1/3 is a direct transcriptional target of PAX6 [6].…”

“…Mutation carriers had an increased proinsulin/insulin ratio and reduced insulin response to an OGTT [6]. By generating mice with a corresponding stop-mutation, the authors could demonstrate that PAX6 deficiency reduced the production of prohormone convertase (PC)1/3 and that the PCSK1 gene encoding PC1/3 is a direct transcriptional target of PAX6 [6]. Confusingly, another study reported that mice lacking Pax6 developed diabetes but had normal PC1/3 levels, making the role of PAX6 in PCSK1 transcription unclear [7].…”