Activation of the HIF1?/PFKFB3 stress response pathway in beta cells in type 1 diabetes.

ABSTRACT:

Aims/hypothesis

The conserved hypoxia inducible factor 1 ? (HIF1?) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1? signalling pathway.

Methods

RNA sequencing (RNA-Seq) data from human islets with type 1 diabetes or after cytokine exposure in vitro was evaluated for activation of HIF1? targets. This was corroborated by immunostaining human pancreases from individuals with type 1 diabetes for 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the key effector of HIF1?-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes.

Results

HIF1? signalling is activated (p?=?4.5?×?10^-9) in islets from individuals with type 1 diabetes, and in human islets exposed in vitro to cytokines implicated in type 1 diabetes (p?=?1.1?×?10^-14). Expression of PFKFB3 is increased fivefold (p?Conclusions/interpretationThe conserved pro-survival HIF1?-mediated injury-response signalling is activated in beta cells in type 1 diabetes and likely contributes to the relatively slow rate of beta cell loss at the expense of early defective glucose-induced insulin secretion.

SUBMITTER: Nomoto H 

PROVIDER: S-EPMC6945783 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature