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

  • Joana Real, Caroline Miranda, Charlotta S. Olofsson, Paul A. Smith
  • Endocrinology Diabetes & Metabolism, March 2018, Wiley
  • DOI: 10.1002/edm2.17

How could statins affect insulin secretion and blood sugar levels

What is it about?

In addtion to drugs, such as sulphonylureas, clinically used to treat type II diabetes, quite a few other drugs classes are also known to increase blood insulin, which in some cases can have the undesired side effect of producing low blood sugar, hypoglycemia, and metabolic dysfunction. Although the underlying biological mechanism of how these drugs achieve this is known: by interacting with a specific membrane protein, KATP, involved in the release process of insulin, to date no obvious relationship between the different stuctures of these drug classes and this shared behaviour existed . We now show that this property simply relates to the the ability of these drugs to dissolve in the lipid (oil) environment of plasma membrane and exert an action on KATP , which can bring about the undesired effect of heightened insulin secretion. We go onto to confirm this idea by using statins a class of drugs that vary in their degree of lipid solubility.

Why is it important?

We demonstrate that Log P, a measure of lipophilicity, can be used as a fascile tool to predict the potency of a drug to affect KATP and stimulate inuslin release without the need to consider complex quantitative structural activity relationships with how the drug interact with KATP. This research suggests that the Log P of a drug can be used as a simple aid to predict the potential of a drug, new or old, to intact with KATP and the cellular process of insulin release and maybe cause hypoglycemia in the clinic. However, in order for this action consideration of the therapeutic dose employed as well as the ability of the drug to bind to plasma serum are required

Perspectives

Paul Smith
University of Nottingham

I was surprised by the simplicity of such an important finding. In fact we have since found other drugs that conform to this idea and have been associated with metabolic disturbance under conditions that fulfil our criteria

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http://dx.doi.org/10.1002/edm2.17

The following have contributed to this page: Paul Smith