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Glucose-induced cytosolic pH changes in beta-cells and insulin secretion are not causally related: studies in islets lacking the Na+/H+ exchangeR NHE1.

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Stiernet, Patrick Nenquin, Myriam [UCL] Moulin, Pierre Jonas, Jean-Christophe [UCL] Henquin, Jean-Claude [UCL]

The contribution of Na(+)/H(+) exchange (achieved by NHE proteins) to the regulation of beta-cell cytosolic pH(c), and the role of pH(c) changes in glucose-induced insulin secretion are disputed and were examined here. Using real-time PCR, we identified plasmalemmal NHE1 and intracellular NHE7 as the two most abundant NHE isoforms in mouse islets. We, therefore, compared insulin secretion, cytosolic free Ca(2+) ([Ca(2+)](c)) and pH(c) in islets from normal mice and mice bearing an inactivating mutation of NHE1 (Slc9A1-swe/swe). The experiments were performed in HCO(-)(3)/CO(2) or HEPES/NaOH buffers. PCR and functional approaches showed that NHE1 mutant islets do not express compensatory pH-regulating mechanisms. NHE1 played a greater role than HCO(-)(3)-dependent mechanisms in the correction of an acidification imposed by a pulse of NH(4)Cl. In contrast, basal pH(c) (in low glucose) and the alkalinization produced by high glucose were independent of NHE1. Dimethylamiloride, a classic blocker of Na(+)/H(+) exchange, did not affect pH(c) but increased insulin secretion in NHE1 mutant islets, indicating unspecific effects. In control islets, glucose similarly increased [Ca(2+)](c) and insulin secretion in HCO(-)(3) and HEPES buffer, although pH(c) changed in opposite directions. The amplification of insulin secretion that glucose produces when [Ca(2+)](c) is clamped at an elevated level by KCl was also unrelated to pH(c) and pH(c) changes. All effects of glucose on [Ca(2+)](c) and insulin secretion proved independent of NHE1. In conclusion, NHE1 protects beta-cells against strong acidification, but has no role in stimulus-secretion coupling. The changes in pH(c) produced by glucose involve HCO(-)(3)-dependent mechanisms. Variations in beta-cell pH(c) are not causally related to changes in insulin secretion.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès libre
Publication date 2007
Journal information "The Journal of biological chemistry" - Vol. 282, no. 34, p. 24538-46 (2007)
Peer reviewed yes
issn 0021-9258
Publication status Publié
Affiliation UCL - MD/FSIO - Département de physiologie et pharmacologie
MESH Subject Animals ; Biological Transport ; Cation Transport Proteins ; Cytosol - metabolism ; Dose-Response Relationship, Drug ; Glucose - metabolism ; Hydrogen-Ion Concentration ; Insulin - metabolism - secretion ; Insulin-Secreting Cells - metabolism ; Membrane Proteins ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Protein Isoforms ; Sodium-Hydrogen Antiporter - metabolism ; Time Factors
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Bibliographic reference Stiernet, Patrick ; Nenquin, Myriam ; Moulin, Pierre ; Jonas, Jean-Christophe ; Henquin, Jean-Claude. Glucose-induced cytosolic pH changes in beta-cells and insulin secretion are not causally related: studies in islets lacking the Na+/H+ exchangeR NHE1.. In: The Journal of biological chemistry, Vol. 282, no. 34, p. 24538-46 (2007)
Permanent URL http://hdl.handle.net/2078.1/12755