Proteomics

Dataset Information

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Fructose-bisphosphatase 1 (FBP1) is a target of the antihyperglycemic action of salicylate


ABSTRACT: Widespread use of the ancient drug salicylate for diabetes in humans has been prevented by challenging side effects of the drug, and continuing uncertainty about the relevant enzyme target(s), against which other drugs could then be developed. Here, we identify fructose-1,6-bisphosphatase 1 (FBP1) as an important contributor to the anti-hyperglycaemic action of salicylate. Compared with wild-type littermates, AMP-insensitive FBP1 knockin (KI) mice, were resistant to effects of the drug on body weight, fasting glucose, glucose tolerance, pyruvate disposal and glucose production. Relative disinhibition of gluconeogenesis in KI hepatocytes led to reductions in TCA cycle activity, linking insulin resistance and its reversal, to non-carbohydrate fuel management. Taken together with previous findings on metformin, the accidental discovery on at least two independent occasions of diabetes drugs capable of promoting allosteric FBP1 inhibition, highlight this target as a highly promising target for prospective rational drug discovery approaches.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte

DISEASE(S): Disease Free

SUBMITTER: Raid Nisr  

LAB HEAD: Graham Rena

PROVIDER: PXD053975 | Pride | 2025-05-26

REPOSITORIES: pride

Dataset's files

Source:
Action DRS
2108306523838.xlsx Xlsx
IP-1.raw Raw
IP-10.raw Raw
IP-11.raw Raw
IP-12.raw Raw
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Publications

The Ancient Drug Salicylate Indirectly Targets Fructose-1,6-Bisphosphatase to Suppress Liver Glucose Production in Diet-Induced Obese Mice.

Nisr Raid B RB   Atrih Abdelmadjid A   Lara Erika J Gutierrez EJG   Lamont Douglas D   Luda Katarzyna M KM   McCrimmon Rory J RJ   Sakamoto Kei K   Rena Graham G   McNeilly Alison D AD  

Acta physiologica (Oxford, England) 20250601 6


<h4>Aims</h4>The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets mediating its anti-hyperglycaemic effect may lead to the development of novel therapies for diabetes. Here, we investigated the contribution of 5'-adenosine monophosphate (AMP)-dependent inhibition of fructose-1,6-bisphosphatase 1 (FBP1) to the anti-hyperglycaemic action o  ...[more]

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