Leech, Colin Anthony, PhD
Interaction of sulfonylureas and incretins to produce hypoglycemia
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Regulation of Food Intake, Obesity\Animal Models, Signal Transduction (Non-Insulin Action)\Hormones
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Sulfonylureas have been used to treat type 2 diabetes for many years and require careful dosing to avoid hypoglycemia. More recently, exenatide and gliptins entered clinical use and, unlike sulfonylureas, their stimulation of insulin secretion is glucose-dependent, reducing the risk of hypoglycemia. Because some type 2 diabetics become insensitive to sulfonylureas over time, combination therapies have been tested as a possible means of improving treatment. Unexpectedly, combinations of sulfonylureas and either exenatide or gliptins significantly increased the risk of hypoglycemia. Sulfonylureas stimulate insulin secretion through binding to a sulfonylurea receptor (SUR1) in beta cells. This binding closes ATP-sensitive potassium channels that are normally closed by glucose metabolism, but this effect of glucose is defective in type 2 diabetics causing insufficient insulin secretion to maintain normal blood glucose. Exenatide and gliptins stimulate cAMP signaling and act through protein kinase A and Exchange protein activated by cAMP (Epac). Epac also binds to SUR1, and sulfonylureas might also directly activate Epac, indicating common targets where drug intera+W3ctions could occur. Our data indicates that Epac activation increases the sensitivity of beta cells to sulfonylureas and we propose that this could explain the increased incidence of hypoglycemia when sulfonylureas and exenatide or gliptins are combined. The aims of this proposal are to investigate the mechanism underlying this drug interaction as it could allow the effective use of lower doses, reducing the risk of both failure and adverse side effects. We also propose an alternative drug combination that could enhance insulin secretion in type 2 diabetics.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and or/curing diabetes?
This project involves the study of drug interactions to stimulate insulin secretion. Our studies aim to identify combinations of drugs that can be safely used to treat type 2 diabetes that are more effective than drugs used alone. This project will specifically identify points of interaction where signaling pathways activated by various drugs promote insulin secretion.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our research aims to identify combinations of drugs that can be safely used to treat type 2 diabetes by stimulating insulin secretion. The use of drug combinations we believe will allow the use of lower doses reducing the risk of adverse side effects and of drug desensitization.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have family members with type 2 diabetes. This award will fund research into novel drug therapies to provide improved treatments for type 2 diabetes.
In what direction do you see the future of diabetes research going?
There is much that remains unknown about the pathophysiological changes that cause diabetes in both defective insulin secretion and insulin resistance. A more complete understanding of the signaling pathways that regulate insulin secretion and action will identify novel targets for drug development to treat or cure diabetes.
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