GNF4877

High glucose concentrations and glucokinase activators (GKAs) increase Ca ²⁺ signalling in β-cells, and increase intracellular Ca ²⁺ leads to activation of calcineurin and nuclear translocation of NFATc proteins. Indeed, concentrations of GNF4877 ((0.1 μM, 0.3 μM) well below the EC ₅₀ for β-cell proliferation are able to induce proliferation in the presence of high glucose or pharmacological activators of glucokinase. Finally, increasing intracellular Ca ²⁺ with glibenclamide (a sulfonylurea receptor 1 inhibitor) or Bay K8644 (an L-type Ca ²⁺ sup> channel activator) show additive activity with GNF4877.

GNF4877 (50 mg/kg; oral gavage; twice a day; for 15 days; double transgenic RIP-DTA male mice) treatment induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control.