β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes

Lalwani, Amit; Warren, Joanna; Liuwantara, David; Hawthorne, Wayne J.; O’Connell, Philip J.; Gonzalez, Frank J.; Stokes, Rebecca; Chen, Jennifer; Laybutt, D. Ross; Craig, Maria E.; King, Charles M.; Gunton, Jenny E.

doi:10.1016/j.celrep.2019.04.086

Cited by 24 publications

(17 citation statements)

References 74 publications

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“…Interestingly, reduced HIF-1α and HIF-1β expression have been observed in the islets of individuals with type 2 diabetes, suggesting that islet HIF-1 inhibition may be a pathogenic mechanism in type 2 diabetes [ 38 , 40 ]. 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 ].…”

Section: Hypoxia and Hifs In Diabetes And Diabetes Complicationsmentioning

confidence: 99%

Hypoxia and hypoxia-inducible factors in diabetes and its complications

2021

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Hypoxia-inducible factors (HIFs) are the key regulators of oxygen homeostasis in response to hypoxia. In diabetes, multiple tissues are hypoxic but adaptive responses to hypoxia are impaired due to insufficient activation of HIF signalling, which results from inhibition of HIF-1α stability and function due to hyperglycaemia and elevated fatty acid levels. In this review, we will summarise and discuss current findings about the regulation of HIF signalling in diabetes and the pathogenic roles of hypoxia and dysregulated HIF signalling in the development of diabetes and its complications. The therapeutic potential of targeting HIF signalling for the prevention and treatment of diabetes and related complications is also discussed. Graphical abstract

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Section: Hypoxia and Hifs In Diabetes And Diabetes Complicationsmentioning

confidence: 99%

Hypoxia and hypoxia-inducible factors in diabetes and its complications

2021

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“…Interestingly, loss of β cell HIF-1α increases risk of T1D. NOD mice (a model of T1D) have low rates of diabetes development after exposure to the β cell toxin streptozotocin or to viruses associated with human diabetes (41). In NOD mice, loss of HIF-1α in β cells makes β cells more susceptible to death, increasing the risk of spontaneous T1D and the risk of T1D after streptozotocin or coxsackievirus exposure (41).…”

Section: R E V I E W S E R I E S : H Y P O X I a -I N D U C I B L E F A C T O R S I N D I S E A S E Pat H O P H Y S I O L O G Y A N D T Hmentioning

confidence: 99%

Hypoxia-inducible factors and diabetes

Gunton¹

2020

Journal of Clinical Investigation

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“…We recently established that the slow time course of beta cell loss in type 2 diabetes, along with a predominant defect in glucose-stimulated insulin secretion, is at least partially attributable to activation of a highly conserved stress-induced prosurvival hypoxia inducible factor 1 α (HIF1α)/ 6phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signalling pathway [5]. Deletion of Hif1a increases vulnerability of beta cells to viral infections and toxins and increases the incidence of autoimmune diabetes in the NOD mouse model [6]. A genetic variant of HIF1α that increases activation of HIF1α in response to stress is less common in type 1 and type 2 diabetes than in non-diabetic conditions, consistent with a protective role of HIF1α against beta cell stress [7,8].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes

Cited by 24 publications

References 74 publications

Hypoxia and hypoxia-inducible factors in diabetes and its complications

Hypoxia and hypoxia-inducible factors in diabetes and its complications

Hypoxia-inducible factors and diabetes

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

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