Abstract
BackgroundAmiloride 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.MethodsUsing 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.ResultsA 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.ConclusionIslets 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.
Highlights
Amiloride derivatives, commonly used for their diuretic and antihypertensive properties, can cause a sustained but reversible decrease of intracellular pH
Regulation of islet pHi and the influence of amiloride derivatives on insulin secretion and time-dependent potentiation (TDP) in isolated islets from diabetic mice were compared to similar parameters in islets from wild type mice. Results from both models of type 2 diabetes demonstrate some abnormalities in pHi-regulation, and consistently favorable effects of dimethyl amiloride (DMA)/amiloride on both direct insulin secretion and TDP in isolated islets
These results suggest the potential value of amiloride derivatives in treatment of type 2 diabetes
Summary
Commonly used for their diuretic and antihypertensive properties, can cause a sustained but reversible decrease of intracellular pH (pHi). Nutrient-stimulated insulin secretory response in the pancreatic β cell consists of three distinct components These include: a) an initial peak (first phase) triggered by Ca2+, b) augmentation of the Ca2+-triggered response (second phase), and c) a memory that persists after removal of the nutrient, causing enhancement of subsequent secretory responses (time-dependent potentiation) [1,2,3,4]. BMC Endocrine Disorders 2005, 5:9 http://www.biomedcentral.com/1472-6823/5/9 small pool of secretory granules, producing the initial peak of the insulin response [1] This peak is followed by a sustained second phase of insulin release that lasts through the duration of exposure to the nutrient, mediated through augmentation of the Ca2+-triggered firstphase response [1]. Time-dependent potentiation (TDP), a positive memory induced during this acute response, magnifies subsequent secretory responses to all secretagogues [2,4,5,6]
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