Non-steroidal anti-inflammatory drugs increase insulin release from beta cells by inhibiting ATP-sensitive potassium channels

Li J, Zhang N, Ye B, Ju W, Orser B, Fox JE, Wheeler MB, Wang Q, Lu WY. (2007) Br J Pharmacol. 151(4):483-93.


BACKGROUND AND PURPOSE: Some non-steroidal anti-inflammatory drugs (NSAIDs) incidentally induce hypoglycemia, which is often seen in diabetic patients receiving sulphonylureas. NSAIDs influence various ion channel activities, thus they may cause hypoglycemia by affecting ion channel functions in insulin secreting beta cells. This study investigated the effects of the NSAID meclofenamic acid (MFA) on the electrical excitability and the secretion of insulin from pancreatic beta cells.

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 Ca2+ imaging displayed that MFA elevated intracellular Ca2+ 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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