Luteolin and kaempferol promote insulin secretion in islet and improve hyperglycemia through IL18-NCC signaling in mice

Interleukin 18 (IL18)-Na-Cl cotransporter (NCC) signaling triggers β cell proliferation, development survival and insulin production in islets. Targeting islet insulin production is a potential strategy for hyperglycemia treatment. Dietary flavonoids possess the substantial anti-hyperglycemia activity. However, whether these flavonoids improve hyperglycemia through directly promoting islet insulin production and the underlying mechanism remains unclear. In this study, islets are isolated from wild-type (WT) and Ncc^-/- mice and treated with dietary flavonoids ex vivo. Among the six dietary flavonoids of chrysin, apigenin, luteolin, quercetin, myricetin and kaempferol, 10 μM luteolin and kaempferol exhibit the highest activities in stimulating insulin production in ex vivo islet. Furthermore, luteolin and kaempferol treatments increase IL18 production and NCC expression, enhance β cell proliferation and survival, protect against streptozocin (STZ)-induced apoptosis and damage in islet. However, the deficiency of NCC eliminate these activities of luteolin and kaempferol. Moreover, STZ-induced hyperglycemic mice are fed a diet supplemented with 0.01% luteolin or kaempferol. In vivo studies have shown that dietary supplementation with luteolin or kaempferol improves glucose tolerance and insulin production, alleviates the apoptosis of islet β cells, and elevates IL18 expression in STZ-induced hyperglycemic mice. In conclusion, dietary luteolin and kaempferol promote islet insulin production, proliferation and survival, protect against STZ-induced islet apoptosis and hyperglycemia through IL18-NCC signaling.