Diphenylhydantoin suppresses glucose-induced insulin release by decreasing cytoplasmic H+ concentration in pancreatic islets

Endocrinology
Koichiro NabeNobuya Inagaki

Abstract

Diphenylhydantoin (DPH), which is clinically used in the treatment of epilepsy, inhibits glucose-induced insulin release from pancreatic islets by a mechanism that remains unknown. In the present study, DPH is shown to suppress glucose-induced insulin release concentration-dependently. In dynamic experiments, 20 microm DPH suppressed 16.7 mm glucose-induced biphasic insulin release. DPH also suppressed insulin release in the presence of 16.7 mm glucose, 200 microm diazoxide, and 30 mm K+ without affecting the intracellular Ca2+ concentration. DPH suppressed ATP content and mitochondrial membrane hyperpolarization in the presence of 16.7 mm glucose without affecting glucose utilization, glucose oxidation, and reduced nicotinamide adenine dinucleotide phosphate fluorescence. DPH increased cytoplasmic pH in the presence of high glucose, but the increase was abolished under Na+ -deprived conditions and HCO3- -deprived conditions, suggesting that Na+ and HCO3- transport across the plasma membrane are involved in the increase in cytoplasmic pH by DPH. Alkalization by adding NH4+ to the extracellular medium also suppressed insulin release, ATP content, and mitochondrial membrane hyperpolarization. Because ATP production from the mitoc...Continue Reading

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Citations

May 15, 2012·The Journal of Endocrinology·Bruno LefebvreFrancois Pattou
May 21, 2014·Current Opinion in Nephrology and Hypertension·Christine DeislDaniel G Fuster
Dec 14, 2011·Expert Opinion on Drug Metabolism & Toxicology·Josef Finsterer, Sinda Zarrouk Mahjoub
Sep 25, 2012·Biochemical and Biophysical Research Communications·Yan-Ming SunLan-Feng Wang
Nov 18, 2008·Metabolism: Clinical and Experimental·Regje M E BlümerPeter F Dubbelhuis
Apr 24, 2007·Diabetes Research and Clinical Practice·Shimpei FujimotoYutaka Seino
Jul 15, 2017·Pediatrics International : Official Journal of the Japan Pediatric Society·Lerlak WitthayapraphakornVichit Supornsilchai
Jan 2, 2019·International Journal of Molecular Sciences·Nicola Baldini, Sofia Avnet
May 3, 2012·American Journal of Physiology. Endocrinology and Metabolism·M WillenborgI Rustenbeck
Oct 18, 2007·Current Opinion in Endocrinology, Diabetes, and Obesity

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