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A Method for Regulating Glucokinase by Reaction With Nitric Oxide
Vanderbilt researchers have discovered a novel mechanism through which the insulin regulating enzyme glucokinase is regulated. This discovery provides a powerful way to screen for activators of glucokinase, which may lead to therapies for diabetes.
Diabetes is a disease that affects over 20 million people in the United States and contributed to 224,092 deaths in 2002, according to the American Diabetes Association. Diabetes is characterized by persistent hyperglycemia, resulting from either defective secretion or action of insulin, the hormone responsible for converting sugar in the blood into energy. The mechanisms and actions of insulin are under intense research to combat this disease.
Studies have shown that the enzyme glucokinase (GK) plays a major role in stimulating beta cell insulin release. Recently this enzyme has been shown to associates with secretory granules when glucose levels are low. Thus, this association correlates with a decrease in GK activity or an inactive form of GK. Exposure to high levels of glucose causes GK to undergo conformational changes and dissociate from the granule. This is the active form of the GK enzyme and therefore stimulates insulin release. Insulin levels can promote these changes in GK, as well.
These Vanderbilt investigators have determined a novel and previously unknown method for regulating GK activity in pancreatic beta cells through their reaction with nitric oxide. Using quantitative imaging of multi-color fluorescent proteins fused to GK, the researchers found that the association with GK and secretory granules is modulated by nitric oxide. Cells exposed to nitric oxide display activated GK, and thus stimulate insulin release. This novel and previously undetermined method of regulating GK allows a way to screen for new GK activators. Previously, Hoffman- LaRoche published a glucokinase activator, which, in preclinical trials, lowered blood sugar levels. This GK activator not only stimulates the pancreas to release more insulin, but it also prevents the liver from producing too much glucose. Currently this type of dual action cannot be achieved in one drug, and patients must take two different drugs, sulfonylureas and melformin, to achieve these results. Thus, GK activators may be a potent treatment for diabetes. Dr. Piston's group has discovered a novel method for identifying additional activators of GK by understanding the regulation of GK. This discovery provides an important tool to discover an entire class of potentially valuable therapies in which to combat diabetes.
Potential Market Size
Diabetes is the 5th leading cause of death by disease in the U.S. and contributes to higher rates of morbidity such that people with diabetes are at higher risk for heart disease, blind ness, kidney failure, extremity amputations and other chronic conditions. A report from the American Diabetes Association funded by the NIH estimated the total annual economic cost of diabetes in 2002 to be $132 billion.
Current Competitive Products
Currently there are medications available to treat diabetes. Two common drug types, sulfonylureas and meglitinides, are often prescribed in combination in order to increase insulin production and reduce glucose production. Often drug combinations result in increased side effects, though. Furthermore, many patients are allergic to sulfa drugs and are unable to take sulfonylureas. Therefore, a new target to increase insulin release will allow more flexibility for clinicians and possibly more effective treatment options for patients.
Intellectual Property Status
U.S. Patent # 7,179,613 was issued on February 20, 2007, with claims directed towards a method of screening for a modulator of glucokinase.
Inventors:David PistonMark Rizzo