[HTML][HTML] Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes
H Nomoto, L Pei, C Montemurro, M Rosenberger… - Diabetologia, 2020 - Springer
H Nomoto, L Pei, C Montemurro, M Rosenberger, A Furterer, G Coppola, B Nadel…
Diabetologia, 2020•SpringerAims/hypothesis The conserved hypoxia inducible factor 1 α (HIF1α) 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 HIF1α 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 HIF1α targets. This was …
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 HIF1α 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 HIF1α targets. This was …
Aims/hypothesis
The conserved hypoxia inducible factor 1 α (HIF1α) 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 HIF1α 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 HIF1α 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 HIF1α-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes.
Results
HIF1α 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 < 0.01) in beta cells in type 1 diabetes and in human and rat islets exposed to cytokines that induced increased lactate production. HIF1α attenuates cytokine-induced cell death in beta cells.
Conclusions/interpretation
The conserved pro-survival HIF1α-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.
Springer