Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: Using patch clamp techniques and insulin secretion assays, the effects of MFA on the membrane potential and transmembrane current of INS-1 cells, and insulin secretion were studied. KEY RESULTS: Under perforated patch recordings, MFA induced a rapid depolarization in INS-1 cells bathed in low (2.8 mM), but not high (28 mM) glucose solutions. MFA, as well as acetylsalicylic acid (ASA) and flufenamic acid (FFA), excited the cells by inhibiting ATP-sensitive potassium channels (K( ATP)). In whole cell recordings, K( ATP) conductance consistently appeared when intracellular ATP was diluted. Intracellular glibenclamide prevented the development of K( ATP) activity, whereas intracellular MFA had no effect. At low glibenclamide concentrations, MFA induced additional inhibition of the K( ATP) current. Live cell Ca(2+) imaging displayed that MFA elevated intracellular Ca(2+) at low glucose concentrations. Furthermore, MFA dose-dependently increased insulin release under low, but not high, glucose conditions. CONCLUSIONS AND IMPLICATIONS: MFA blocked K( ATP) through an extracellular mechanism and thus increased insulin secretion. As some NSAIDs synergistically inhibit K( ATP) activity together with sulphonylureas, the risk of NSAID-induced hypoglycemia should be considered when glucose-lowering compounds are administered.
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Authors | J Li, N Zhang, B Ye, W Ju, B Orser, J E M Fox, M B Wheeler, Q Wang, W-Y Lu |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 151
Issue 4
Pg. 483-93
(Jun 2007)
ISSN: 0007-1188 [Print] England |
PMID | 17435793
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Insulin
- Potassium Channel Blockers
- Meclofenamic Acid
- Adenosine Triphosphate
- Glucose
- Calcium
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Topics |
- Adenosine Triphosphate
(pharmacology)
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(pharmacology)
- Calcium
(metabolism)
- Cells, Cultured
- Glucose
(pharmacology)
- Insulin
(metabolism)
- Insulin Secretion
- Insulin-Secreting Cells
(drug effects, metabolism, physiology)
- Meclofenamic Acid
(pharmacology)
- Membrane Potentials
(drug effects)
- Mice
- Potassium Channel Blockers
(pharmacology)
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