Thiazides attenuate insulin secretion through inhibition of mitochondrial carbonic anhydrase 5b in β-islet cells in mice

Background: Thiazides are associated with glucose intolerance and new onset diabetes mellitus. Previous studies demonstrated that thiazides attenuate insulin secretion, but the molecular mechanisms remain elusive. We hypothesized that thiazides attenuate insulin secretion via one of the known molecular thiazide targets in β-cells. Methods: We performed static insulin secretion experiments with islets of wild-type, NCC (SLC12A3) and NDCBE (SLC4A8) knock-out (KO) mice and with murine Min6 cells with individual knock-down of carbonic anhydrase (CA) isoforms to identify the molecular target of thiazides in β-cells. CA5b KO mice were then used to assess the role of the putative thiazide target CA5b in β-cell function and in mediating thiazide sensitivity in vitro and in vivo. Results: Thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion in islets and Min6 cells at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO2/HCO3--depen..., ,