Dose Dependent Effect of Sulfamethoxazole on Inhibiting KATP Channel of Mouse Pancreatic ß Cell.

Sulfamethoxazole (SMX) is widely used as an antibiotic in the clinical application with side effects of hypoglycemia. This is because SMX contains the sulfonamide structure, which closes ATP-sensitive potassium (KATP) channels and induces insulin secretion. However, there are no detail reports that measure the effective dose that can close KATP channels and induce insulin secretion. In this study, whole-cell patch clamp recording was utilized to measure the effect of SMX on KATP channel activity on pancreatic ß cells. Also, the static incubation assay with mice islets was assessed to measure the insulin secretion capacity of SMX. SMX was shown to inhibit the KATP channel in pancreatic ß cell membrane and induce insulin secretion in relatively high concentration. The half maximal inhibitory concentration (IC50) for KATP channel activity of SMX was .46 ± .08 mM. It was also shown that a near IC50 concentration of SMX (.5 mM) was able to nearly fully block the KATP channel when simultaneously applied with low concentration sulfonylurea, tolbutamide (.01 mM). Our present data provide important information for the clinical use of SMX to treat infection in diabetic patients using sulfonylureas.

Effect of fenofibrate and selective PPARα modulator (SPPARMα), pemafibrate on KATP channel activity and insulin secretion.

OBJECTIVE: Insulin secretion is regulated by ATP-sensitive potassium (KATP) channels in pancreatic beta-cells. Peroxisome proliferator-activated receptors (PPAR) α ligands are clinically used to treat dyslipidemia. A PPARα ligand, fenofibrate, and PPARγ ligands troglitazone and 15-deoxy-∆12,14-prostaglandin J2 are known to close KATP channels and induce insulin secretion. The recently developed PPARα ligand, pemafibrate, became a new entry for treating dyslipidemia. Because pemafibrate is reported to improve glucose intolerance in mice treated with a high fat diet and a novel selective PPARα modulator, it may affect KATP channels or insulin secretion. RESULTS: The effect of fenofibrate (100 µM) and pemafibrate (100 µM) on insulin secretion from MIN6 cells was measured by using batch incubation for 10 and 60 min in low (2 mM) and high (10 mM) glucose conditions. The application of fenofibrate for 10 min significantly increased insulin secretion in low glucose conditions. Pemafibrate failed to increase insulin secretion in all of the conditions experimented in this study. The KATP channel activity was measured by using whole-cell patch clamp technique. Although fenofibrate (100 µM) reduced the KATP channel current, the same concentration of pemafibrate had no effect. Both fenofibrate and pemafibrate had no effect on insulin mRNA expression.