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Abstract: FR-OR50

Thiazides Induce Glucose Intolerance Through Inhibition of Mitochondrial Carbonic Anhydrase 5b in β-Cells

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic

Authors

  • Kucharczyk, Patrycja, Inselspital Universitatsspital Bern Universitatsklinik fur Nephrologie und Hypertonie, Bern, Bern, Switzerland
  • Albano, Giuseppe, Inselspital Universitatsspital Bern Universitatsklinik fur Nephrologie und Hypertonie, Bern, Bern, Switzerland
  • Fuster, Daniel G., Inselspital Universitatsspital Bern Universitatsklinik fur Nephrologie und Hypertonie, Bern, Bern, Switzerland
Background

Thiazide and thiazide-like diuretics (thiazides) have been the cornerstone for the treatment of arterial hypertension and pharmacologic recurrence prevention of kidney stones for more than 50 years. Hence, not surprisingly, thiazides belong to the most widely prescribed drugs worldwide. Since their introduction into clinical medicine, thiazides are known to be associated with glucose intolerance and new onset diabetes, but the molecular mechanisms remain elusive. The aim of this study was to decipher the molecular basis of thiazide-induced glucose intolerance.

Methods

We employed wild-type and genetically modified mice, primary pancreatic β-cells and murine MIN6 cells to study the impact of thiazides on systemic glucose homeostasis, insulin sensitivity and insulin secretion.

Results

In mice, hydrochlorothiazide induced a pathological glucose tolerance, characterized by reduced first phase insulin secretion but normal insulin sensitivity. In vitro, thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion in islets and the murine β-cell line Min6 at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO2/HCO3--dependent, not additive to unselective carbonic anhydrase (CA) inhibition with acetazolamide and independent of extracellular potassium. In contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC (SLC12A3) or NDCBE (SLC4A8). CA expression profiling with subsequent knock-down of individual CA isoforms suggested mitochondrial CA5b as molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxalacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and insulin secretion of islets isolated from CA5b KO mice was unaffected by thiazides.

Conclusion

Our study reveals attenuated insulin secretion due to inhibition of the mitochondrial CA5b isoform in β-cells as molecular mechanism of thiazide-induced glucose intolerance.

Funding

  • Government Support – Non-U.S.