Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Increasing evidence suggests that loss of beta 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 beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta 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 Ca(2+) 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 beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in humans.

Original publication

DOI

10.1016/j.celrep.2014.11.033

Type

Journal article

Journal

Cell Rep

Publication Date

2014

Volume

9

Pages

2219 - 2232

Keywords

Animals Calcium Channels/genetics/metabolism Cells, Cultured DNA-Binding Proteins/genetics/*metabolism Exocytosis Gene Silencing Glucokinase/genetics/metabolism Glucose/*metabolism Glucose Intolerance/*genetics Insulin/*metabolism Insulin-Secreting Cells/*metabolism Mice Regulatory Factor X Transcription Factors Sulfonylurea Receptors/genetics/metabolism Transcription Factors/genetics/*metabolism