The contrasting effects of two antimalarial drugs on insulin secretion

Quinolines and artemisinins are the two most important antimalarial drugs worldwide. In addition to antimalarial effects, quinine has been extensively documented to directly stimulate insulin secretion, potentially causing hypoglycemia in malaria patients undergoing treatment through the inhibition of K_ATP channels, and artemisinins have been recently identified as small molecules that increase insulin secretion by functionally promoting the conversion of pancreatic α cells into β cells, which is promising for the therapy of diabetes. Here, to detect the precise function of these drugs in insulin secretion, glucose-stimulated insulin secretion (GSIS) test with isolated mouse islets and insulin secretion experiment in mice were performed. Quinine was the most potent insulin secretagogue of all three quinoline drugs tested in this study. Low-dose quinine potentiated insulin secretion in a high glucose-dependent manner through KCNH6 current inhibition rather than through classical K_ATP inhibition. However, artemisinins did not promote insulin secretion in vitro or in vivo. In particular, artemether significantly suppressed insulin secretion, decreased Ca²⁺ influx and the expression levels of β-cell marker genes, contradicting the findings of previous studies suggesting that artemisinins promote the transformation of pancreatic α cells into β cells. Overall, our observations revealed the differential effects of two widely used antimalarial drugs, quinolines and artemisinins, on insulin secretion. Ascertaining the targets by which drugs affect insulin secretion may advance diabetes treatment.