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Endocrine Abstracts (2006) 11 P372

ECE2006 Poster Presentations Diabetes, metabolism and cardiovascular (174 abstracts)

The role of tumour necrosis factor-alpha in insulin-stimulated endothelial nitric oxide production

SA Ritchie , JMC Connell & IP Salt

Glasgow University, Glasgow, United Kingdom.

Insulin resistance states are associated with endothelial dysfunction, but the molecular mechanisms underlying this association are incompletely understood. Impairment of insulin stimulated endothelial NO production is proposed to be a key mechanism in this process. In cultured human aortic endothelial cell (HAEC) models, insulin stimulates an intracellular signalling cascade resulting in activating phosphorylation of Insulin Receptor Substrate-1 (IRS-1), Protein kinase B (PKB / Akt) and endothelial Nitric Oxide Synthase (eNOS), with resultant NO release. The pro-inflammatory adipokine Tumour Necrosis Factor Alpha (TNF-α) is over-expressed in models of insulin resistance, acting in humans to inhibit both insulin-stimulated glucose uptake and endothelial-dependant vasodilatation. Studies in bovine aortic endothelial cells have shown that preincubation with TNF-α inhibits insulin stimulated NO production, with concomitant inhibition of activating phosphorylation of IRS-1, PKB and eNOS but the precise molecular pathway that accounts for the inhibition seen is unclear. Accordingly, we studied the interaction between TNF-α and insulin-mediated NO production in HAECs.

We have demonstrated that pre-incubation with TNF-α inhibits insulin stimulated NO production. In contrast to bovine studies this was not associated with reduced activating phosphorylation of PKB (Ser473) or eNOS (Ser1177). A previously uncharacterised eNOS residue (Ser 617) is phosphorylated in response to insulin and appears to be unaltered by TNF-α preincubation. Phosphorylation of IRS-1 residue Ser 312 has been proposed as a key inhibitory signalling mechanism in insulin resistance in adipocytes and skeletal muscle, however in our model no change was demonstrable. TNF-α activates JNK and IKK, and these kinases may form the intracellular link between TNF-α and insulin signalling. We hypothesise that the reduction in NO production in this model is not solely due to impairment of the insulin signalling cascade. A potential mechanism of action currently being investigated is a reduction in NO bioavailability through ‘quenching’ by superoxide, produced in response to TNF-α.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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