Project PXD053975 Fructose-bisphosphatase 1 (FBP1) is a target of the antihyperglycemic action of salicylate

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.