The glycogenolytic activity of some substituted salicylic acids

Andrews, Muriel M.

doi:10.1042/bj0750298

Cited by 9 publications

(2 citation statements)

References 10 publications

(1 reference statement)

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“…Mitochondrial inhibition has also previously been suggested as an anti-hyperglycaemic mechanism for biguanides [22] and thiazolidinediones [52] . The differences between SA and 2,5/2,6-DHBA we have observed might also account for previous findings that SA but not 2,5- nor 2,6-DHBA reduces liver glycogen stores [53] . In direct comparison, the SA effect on oxygen consumption was at a magnitude that was about half that of DNP, even though twenty times more SA was added than DNP.…”

Section: Discussionsupporting

confidence: 80%

Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug

Cameron

Logie

Patel

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Anti-hyperglycaemic effects of the hydroxybenzoic acid salicylate might stem from effects of the drug on mitochondrial uncoupling, activation of AMP-activated protein kinase, and inhibition of NF-κB signalling. Here, we have gauged the contribution of these effects to control of hepatocyte glucose production, comparing salicylate with inactive hydroxybenzoic acid analogues of the drug. In rat H4IIE hepatoma cells, salicylate was the only drug tested that activated AMPK. Salicylate also reduced mTOR signalling, but this property was observed widely among the analogues. In a sub-panel of analogues, salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes. Both salicylate and 2,6 dihydroxybenzoic acid suppressed TNFα-induced IκB degradation, and in genetic knockout experiments, we found that the effect of salicylate on IκB degradation was AMPK-independent. Previous data also identified AMPK-independent regulation of glucose but we found that direct inhibition of neither NF-κB nor mTOR signalling suppressed glucose production, suggesting that other factors besides these cell signalling pathways may need to be considered to account for this response to salicylate. We found, for example, that H4IIE cells were exquisitely sensitive to uncoupling with modest doses of salicylate, which occurred on a similar time course to another anti-hyperglycaemic uncoupling agent 2,4-dinitrophenol, while there was no discernible effect at all of two salicylate analogues which are not anti-hyperglycaemic. This finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling.

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