title: Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice.
abstract: BACKGROUND
  Amiloride derivatives, commonly used for their diuretic and antihypertensive properties, can also cause a sustained but reversible decrease of intracellular pH (pHi). Using dimethyl amiloride (DMA) on normal rodent pancreatic islets, we previously demonstrated the critical influence of islet pHi on insulin secretion. Nutrient-stimulated insulin secretion (NSIS) requires a specific pHi-range, and is dramatically enhanced by forced intracellular acidification with DMA. Furthermore, DMA can enable certain non-secretagogues to stimulate insulin secretion, and induce time-dependent potentiation (TDP) of insulin release in mouse islets where this function is normally absent. The present study was performed to determine whether pHi-manipulation could correct the secretory defect in islets isolated from mice with type 2 diabetes.
  
  
  METHODS
  Using two mouse models of type 2 diabetes, we compared a) pHi-regulation, and b) NSIS with and without treatment with amiloride derivatives, in islets isolated from diabetic mice and wild type mice.
  
  
  RESULTS
  A majority of the islets from the diabetic mice showed a slightly elevated basal pHi and/or poor recovery from acid/base load. DMA treatment produced a significant increase of NSIS in islets from the diabetic models. DMA also enabled glucose to induce TDP in the islets from diabetic mice, albeit to a lesser degree than in normal islets.
  
  
  CONCLUSIONS
  Islets from diabetic mice show some mis-regulation of intracellular pH, and their secretory capacity is consistently enhanced by DMA/amiloride. Thus, amiloride derivatives show promise as potential therapeutic agents for type 2 diabetes.
authors.affiliation: Department of Molecular Physiology and Biophysics, 702 Light Hall, Vanderbilt University, Nashville, TN 37232, USA. subhadra.gunawardana@vanderbilt.edu
authors.forename: Subhadra C
authors.initials: SC
authors.lastname: Gunawardana
authors.forename: W Steven
authors.initials: WS
authors.lastname: Head
authors.forename: David W
authors.initials: DW
authors.lastname: Piston