Dataset Information

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

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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]

PMID: 40400417

Similar Datasets

Project description:Obesity-induced insulin resistance of the liver is characterised by increased gluconeogenesis, which contributes to elevated blood glucose levels in individuals with type 2 diabetes. Research into how fatty acids induce insulin resistance has commonly focused on the induction of insulin resistance. We hypothesise that by shifting focus to the reversal of an insulin resistant phenotype, novel insights can be made into the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered in parallel with restoration of palmitate-induced deregulation of glucose production using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075mM, 48h) with or without metformin (0.25mM) and sodium salicylate (2mM) in the final 24h of palmitate treatment, and effects on glucose production were determined. Microarray followed by gene set enrichment analysis was performed to investigate pathway regulation. A lipidomic analysis (HPLC-MS/MS) and measurement of secreted bile acids and cholesterol were performed. Reversal of palmitate-induced impairment of glucose production by metformin and sodium salicylate was characterised by down-regulated expression of metabolic pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. Total levels of intracellular and secreted cholesterol and bile acids were not different between impaired and restored glucose production. Total intracellular levels of diacylgycerol, triacylglycerol and cholesterol esters increased with palmitate (impaired glucose production), however, these were not further altered with metformin and sodium salicylate (restored glucose production). Six individual lipid species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. Widespread lipid metabolism changes induced by the reversal of palmitate-induced deregulation of glucose production with metformin and sodium salicylate were identified. While cholesterol and bile acid levels remained unchanged, the flux through these pathways may in part explain these findings. The identification of lipid species containing 18:0 and 18:1 side chains being regulated alongside changes to glucose production may indicate potential mediators of glucose production and insulin resistance.

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