Glucolipotoxicity initiates pancreatic ?-cell death through TNFR5/CD40-mediated STAT1 and NF-?B activation.

ABSTRACT: Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis is associated with, and exacerbated by, obesity and the concomitant-elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in insulin-producing ?-cell mass through activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-?B and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-?B and STAT1 activation is currently poorly defined. Using high-density microarray analysis of the ?-cell transcritptome, we have identified those genes and proteins most sensitive to glucose and fatty acid environment. Our data show that of those potentially able to activate STAT1 or NF-?B pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-?B activity in ?-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-?B activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.

SUBMITTER: Bagnati M 

PROVIDER: S-EPMC5108311 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature