The effect of hydrochlorothiazide on insulin release, 36Cl- fluxes and 45Ca2+ uptake was tested in beta-cell-rich mouse pancreatic islets. 2. At high glucose concentrations (10 and 20 mmol l-1), low concentrations of hydrochlorothiazide (0.1-1.0 mumol l-1) reduced insulin release by 22-42%. At lower glucose concentrations (3-8.5 mmol l-1) insulin release was not affected by the drug. 3. Neither short-term influx (3 min) nor net accumulation (60 min) of 36Cl- in the islets was affected by hydrochlorothiazide (0.1-500 mumol l-1). 4. Glucose-stimulated 45Ca2+ uptake was significantly reduced by hydrochlorothiazide (1-10 mumol l-1). 5. The data suggest that the diabetogenic effect of hydrochlorothiazide, at least in part, can be mediated by direct inhibition of insulin release from the pancreatic beta-cells. The inhibition is not mediated by reduced chloride fluxes but may rather be caused by inhibition of calcium uptake.
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