Research article

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice

Subhadra C Gunawardana , W Steven Head and David W Piston

Department of Molecular Physiology and Biophysics, 702 Light Hall, Vanderbilt University, Nashville, TN 37232, USA

author email corresponding author email

BMC Endocrine Disorders 2005, 5:9doi:10.1186/1472-6823-5-9

Published:	8 December 2005

Abstract

Background

Amiloride derivatives, commonly used for their diuretic and antihypertensive properties, can also cause a sustained but reversible decrease of intracellular pH (pH_i). Using dimethyl amiloride (DMA) on normal rodent pancreatic islets, we previously demonstrated the critical influence of islet pH_i on insulin secretion. Nutrient-stimulated insulin secretion (NSIS) requires a specific pH_i-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 pH_i-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 pH_i 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.

Conclusion

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.