Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Abstract

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.

Hypoxia and hypoxia-inducible factors in diabetes and its complications

“…Indeed, mice with a beta cell-specific HIF-1α deletion are more susceptible to type 1 diabetes after exposure to coxsackieviruses or beta cell toxin [ 41 ]. HIF-1 is also activated in beta cells during the pre-diabetes period of type 1 diabetes, where it is suggested to have a protective role [ 42 ].…”

Towards 3D-Bioprinting of an Endocrine Pancreas: A Building-Block Concept for Bioartificial Insulin-Secreting Tissue

“…20 We hypothesize that INS-1 cells exposed to environmental stress due to the bioprinting process, transient hypoxic conditions, and hyperglycemia may have activated HIF1a/PFKFB3 stress-repair signaling. 21, 22 This transient state is an adaptive, protective metabolic response that slows β-cell death at the expense of β-cell function and activates glycolysis (z-score 2.333, P < .0001) while inhibiting the oxidative phosphorylation (NES - 2.90, P < 0.01). 21, 22 Additional upstream regulator analysis supported the likelihood of our hypothesis identifying glucose (activation z-score 3.835, overlap P < .0001) based on expression of 87 genes in the dataset (see the graphical display of glucose upstream regulator network incl.…”

Meta-analysis of transcriptome datasets: An alternative method to study IL-6 regulation in coronavirus disease 2019

“…In the current outbreak of COVID-19: (i) the CRS caused by IL-6 has been an important cause of death; (ii) patients with heart disease or diabetes mellitus have a high prevalence of death. PFKFB3 has been suggested to have a critical role in diabetes mellitus [45] . We identified PFKFB3 to be enriched in the present study.…”