Beta cell regeneration meets autoimmunity: PAX4 variants in type 1 diabetes

Abstract

Type 1 diabetes may be considered as a disease that results from an imbalance between selective autoimmune destruction of pancreatic beta cells and beta cell regeneration. This gives rise to an intriguing question: is impaired beta cell regeneration in itself an important determinant of susceptibility to type 1 diabetes [1,2]? Two lines of investigation have recently-and more or less independently-investigated the mechanisms that underlie beta cell development and regeneration, and the mechanisms involved in beta cell destruction by immune cells and proinflammatory cytokines. In this issue of Diabetologia, Biason-Lauber and coworkers provide evidence that a genomic variant of PAX4 is linked to the development of type 1 diabetes [3].PAX4 is a member of the Pax family of homeodomain transcription factors that are operative during the development of the endocrine pancreas and have been shown to be essential for beta cell development and beta cell function [4]. In mice, this transcription factor is expressed on or around Day 9 in cells of the dorsal pancreatic rudiment, with peak expression occurring between Day 13 and 15, followed by a decline until birth. PAX4 has been identified as a downstream target of neurogenin 3, another important transcription factor for the development of the endocrine pancreas [4]. Studies on pax4 knock-out mice showed a profound reduction in beta cell mass and a severe diabetic syndrome after birth. Atypically clustered alpha cells and ghrelin-positive cells were detected in the pancreas, and it was concluded that PAX4 suppresses the development of these cell types [4].The pivotal role played by PAX4 in beta cell development and function has prompted genetic linkage analyses of this gene in cohorts of diabetic patients, with particular focus on type 2 diabetes. These studies yielded conflicting results. Screening of French MODY families showed no linkage between type 2 diabetes and markers of PAX4 [5]. Although the P321H missense mutation was not associated with MODY diabetes, it does seem to be linked to susceptibility to type 1 diabetes, as discussed below. A recent study reported a linkage between a homozygous missense mutation (R121W) in PAX4 and type 2 diabetes in a Japanese population [6]. The mutant allele occurred at a low frequency (2.0%) within this population [6], and Kanatsuka and coworkers described the same PAX4 mutation in patients with late-onset type 2 diabetes [7]. Interestingly, this mutation was associated with impaired first-phase insulin secretion, providing further evidence for the involvement of PAX4 in beta cell function [7]. However, it is not clear from these studies whether the R121W PAX4 missense mutation, whose functional effects have not been demonstrated in insulinproducing cells, may affect beta cell mass in these patients.What is the situation in type 1 diabetes? Through microsatellite analysis of Scandinavian multiplex families, Holm and co-workers demonstrated a linkage between type 1 diabetes and a region on chromosome 7 (7q32) that carries PAX4, but ...

Reply to comment on: Biason-Lauber A, Boehm B, Lang-Muritano M et al. (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia 48:900–905

“…Further studies, such as those outlined by M. Tiedge in his commentary on our study [12], are necessary and are currently underway to identify other components of this pathophysiological network.…”