Journal
DIABETOLOGIA
Volume 63, Issue 1, Pages 149-161Publisher
SPRINGER
DOI: 10.1007/s00125-019-05030-5
Keywords
Cytokines; HIF1 alpha; PFKFB3; Type 1 diabetes
Categories
Funding
- NIH [DK059579]
- Larry L. Hillblom Foundation Network Grant [2014-D-001-NET]
- Larry L. Hillblom Foundation Start-up Grant [2017-D-002-SUP]
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Aims/hypothesis The conserved hypoxia inducible factor 1 alpha (HIF1 alpha) 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 alpha 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 alpha 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 alpha-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 alpha signalling is activated (p = 4.5 x 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 x 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. HIF1 alpha attenuates cytokine-induced cell death in beta cells. Conclusions/interpretation The conserved pro-survival HIF1 alpha-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.
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