Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells

Abstract

SummaryIncreasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2+ channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of “disallowed” genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans.

Human pancreas development

“…RFX6 transcripts were detected progressively in normal human fetal pancreas from the end of embryogenesis, similar to the onset of NEUROG3 and insulin transcription (Lyttle et al, 2008;Smith et al, 2010;Jennings et al, 2013). More recently, RFX6 has been shown to regulate components in the insulin secretory pathway in differentiated β-cells (Chandra et al, 2014;Piccand et al, 2014).…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…We observed significant reductions in immature cells of essential beta cell genes, including many genes required for glucose-stimulated insulin secretion, the TCA cycle and oxidative phosphorylation ( Figure 3A-D). In contrast, key metabolic genes that are either considered 'disallowed' or contribute to their regulation (Dhawan et al, 2015;MartinezSanchez et al, 2016;Piccand et al, 2014;Pullen and Rutter, 2013) were enriched in immature beta cells ( Figure 3E). Islets were also co-stained for insulin, Ucn3, and 8 G6pc2, which hydrolyzes glucose-6-phosphate (Pound et al, 2013) or the oxidoreductase Ero1lb, which is required for disulfide bond formation in pro-insulin (Zito et al, 2010).…”

PAX6 maintains β cell identity by repressing genes of alternative islet cell types

“…Interestingly, the loss of β cell differentiation is often accompanied by acquisition of alternative cellular identities (5,8,9), reflecting the retention of some developmental plasticity in differentiated β cells. Typically, these alternative fates remain within the endocrine lineage.…”