Lipophilicity predicts the ability of nonsulphonylurea drugs to block pancreatic beta-cell KATP channels and stimulate insulin secretion; statins as a test case

Endocrinology, Diabetes & Metabolism
Joana RealPaul A Smith

Abstract

KATP ion channels play a key role in glucose-stimulated insulin secretion. However, many drugs block KATP as "off targets" leading to hyperinsulinaemia and hypoglycaemia. As such drugs are often lipophilic, the aim was to examine the relationship between drug lipophilicity (P) and IC 50 for KATP block and explore if the IC 50's of statins could be predicted from their lipophilicity and whether this would allow one to forecast their acute action on insulin secretion. A meta-analysis of 26 lipophilic, nonsulphonylurea, blockers of KATP was performed. From this, the IC 50's for pravastatin and simvastatin were predicted and then tested experimentally by exploring their effects on KATP channel activity via patch-clamp measurement, calcium imaging and insulin secretion in murine beta cells and islets. Nonsulphonylurea drugs inhibited KATP channels with a Log IC 50 linearly related to their logP. Simvastatin blocked KATP with an IC 50 of 25 nmol/L, a value independent of cytosolic factors, and within the range predicted by its lipophilicity (21-690 nmol/L). 10 μmol/L pravastatin, predicted IC 50 0.2-12 mmol/L, was without effect on the KATP channel. At 10-fold therapeutic levels, 100 nmol/L simvastatin depolarized the beta-cell membr...Continue Reading

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Citations

Mar 13, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Liam CurryPaul A Smith
Dec 20, 2018·Journal of Cellular Physiology·Mohammad Javad Saeedi BorujeniAmid Yazdani
Jul 28, 2020·Journal of the Endocrine Society·Karen J Rees-MiltonRachel M Holden

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Methods Mentioned

BETA
ELISA

Software Mentioned

PRISM
pClamp
Clampfit
GraphPad

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