Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes
| Autor: | Giovanni Coppola, Allison E. Furterer, Hiroshi Nomoto, Chiara Montemurro, Brian B. Nadel, Peter C. Butler, Tatyana Gurlo, Madeline Rosenberger, Lina Pei, Matteo Pellegrini, Slavica Tudzarova |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Phosphofructokinase-2 Endocrinology Diabetes and Metabolism medicine.medical_treatment Type 2 diabetes 0302 clinical medicine PFKFB3 Insulin-Secreting Cells 80 and over 2.1 Biological and endogenous factors Prediabetes HIF1α Aetiology Child Aged 80 and over Tumor Blotting Diabetes Immunohistochemistry Hedgehog signaling pathway Cytokine Type 1 diabetes Public Health and Health Services Cytokines Female Hypoxia-Inducible Factor 1 Beta cell Western Type 1 Signal Transduction Adult medicine.medical_specialty Programmed cell death Blotting Western Clinical Sciences 030209 endocrinology & metabolism Biology alpha Subunit Article Cell Line Paediatrics and Reproductive Medicine 03 medical and health sciences Young Adult Endocrinology & Metabolism Cell Line Tumor Internal medicine Internal Medicine medicine Diabetes Mellitus Animals Humans Immunoprecipitation Beta (finance) HIF1 alpha Metabolic and endocrine Aged Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Rats Diabetes Mellitus Type 1 030104 developmental biology Endocrinology |
| Zdroj: | Diabetologia, vol 63, iss 1 Diabetologia |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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