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Why do sulfonylureas fail amongst people with type 2 diabetes?

October 27, 2008

Sulfonylurea drugs, such as glibenclamide, are widely used for the treatment of type 2 diabetes. These drugs work by causing pancreatic beta cells to release insulin, which occurs when the drug inhibits ATP-sensitive potassium channels, causing calcium to enter the beta cells which then stimulates release of insulin, and consequently a fall in blood glucose levels. However, long term treatment with sulfonylureas eventually fails, but the mechanism is not known.

In a series of mouse experiments published in this issue of PLoS Medicine, Maria Remedi and Colin Nichols from the Washington University School of Medicine explore the mechanisms underlying this treatment failure, and suggest how that failure might be prevented. Their results show that the failure of treatment is not due to sulfonylurea treatment causing death of the pancreatic beta cells, but rather permanent depolarization of the beta cell potassium channels. These studies also show that in mice treated with slow-release sulfonylureas, failure to release insulin is reversible on removal of drug treatment.

The findings suggest that new approaches to sulfonylurea dosing, for example testing low-doses or pulsed doses, may prevent treatment failure. However, new treatment approaches would need to be evaluated first in animals before progressing to clinical testing.

The implications of this study are discussed in a linked Perspective by Erik Renstrom and colleagues from Lund University.
Citation: Remedi MS, Nichols CG (2008) Chronic antidiabetic sulfonylureas in vivo: Reversible effects on mouse pancreatic b-cells. PLoS Med 5(10): e206. doi:10.1371/journal.pmed.0050206



Colin Nichols
Washington University School of Medicine
Cell Biology and Physiology, Box 8228
660 South Euclid Avenue
Saint Louis, MO 63110
United States of America
+1 314-362-6630
+1 314-362-7463 (fax)

Related PLoS Medicine Perspective:

Citation: Rosengren A, Jing X, Eliasson L, Renström E (2008) Why treatment fails in type 2 diabetes. PLoS Med 5(10): e215. doi:10.1371/journal.pmed.0050215



Erik Renstrom
Lund University
CRC-91-11, ing 72
Malmö, Skane SE-20502
+46-46 2220000


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