Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger for mobilizing Ca(2+) from intracellular stores in various cell types. Extracellular application of NAADP has been shown to elicit intracellular Ca(2+) signals, indicating that it is readily transported into cells. However, little is known about the functional role of this NAADP uptake system. Here, we show that NAADP is effectively transported into selected cell types involved in glucose homeostasis, such as adipocytes and pancreatic β-cells, but not the acinar cells, in a high glucose-dependent manner. NAADP uptake was inhibitable by Ned-19, a NAADP mimic; dipyridamole, a nucleoside inhibitor; or NaN3, a metabolic inhibitor or under Ca(2+)-free conditions. Furthermore, NAADP was found to be released from pancreatic islets upon stimulation by high glucose. Consistently, administration of NAADP to type 2 diabetic mice improved glucose tolerance. We propose that NAADP is functioning as an autocrine/paracrine hormone important in glucose homeostasis. NAADP is thus a potential antidiabetic agent with therapeutic relevance.
Highlights
External application of a Ca2ϩ-mobilizing messenger, Nicotinic acid adenine dinucleotide phosphate (NAADP), to -cells activates intracellular Ca2ϩ changes and stimulates insulin secretion
We found that NAADP was increased with a peak at 5–10 min and slowly decreased, suggesting that exogenously administrated NAADP was retained as an intact form in the blood, which could be transported into the cells
Glucose-dependent increase of NAADP uptake was selectively occurring in the glucose-metabolizing organs, suggesting that the NAADP uptake system may play a physiological role in glucose homeostasis
Summary
External application of a Ca2ϩ-mobilizing messenger, NAADP, to -cells activates intracellular Ca2ϩ changes and stimulates insulin secretion. Results: NAADP is transported into adipocytes and -cells in a glucose-dependent manner and is released from pancreatic islets upon stimulation by high glucose. Likewise, Ned, a membrane-permeant and selective antagonist of the NAADP receptor, inhibits the glucose-evoked calcium spiking in mouse pancreatic -cells in a concentration-dependent manner [17] These results indicate a central role for NAADP in the glucose-induced Ca2ϩ signaling in these cells. In adipocytes, activation of the insulin receptor by insulin elicits an increase in endogenous NAADP that coincides with the Ca2ϩ signaling, resulting in glucose uptake [20] that was inhibitable by Ned-19. We have investigated the issue of NAADP transport and found that it efficiently occurs in both pancreatic islets and adipocytes in a glucose-dependent manner, resulting in stimulation of insulin release and glucose uptake, respectively. Our results indicate that NAADP is an autocrine/paracrine signal that can be exploited as a potential antidiabetic agent
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