Scientists at Weill Cornell Medical College in Qatar have discovered how a diabetes drug that has been widely prescribed for more than 50 years protects patients' circulatory systems from damage caused by high blood sugar.
Metformin, the hypoglycemic drug prescribed to most patients with type 2 diabetes, interacts with a family of enzymes that has regulatory control over a wide range of critical cellular functions. The interaction between metformin and the enzymes, called sirtuins, protects patients from irreversible damage to the insulin-producing pancreatic beta cells caused by high blood sugars, an effect known as glucose toxicity.
The study was published online last month in the British Journal of Pharmacology by Weill Cornell-Qatar's Dr. Chris Triggle, professor of pharmacology; Dr. Hong Ding, assistant research professor of pharmacology; and postdoctoral fellow and lead author Dr. Gnanapragasam Arunachalam.
"Our publication not only enhances our knowledge of how treatment with metformin reduces cardiovascular risk in patients with type 2 diabetes, but also provides a potential target for new therapeutic entities that can mimic metformin's action on sirtuin1," a protein in the sirtuin family, said Dr. Triggle, who is the lead principal investigator of a Qatar Foundation-sponsored National Priorities Research Program project exploring the effects of diabetes on the vascular system.
Metformin was first introduced in 1958 to treat type 2 diabetes. It has fewer serious side effects than other diabetes medications, significantly less risk of causing low blood sugar than other drugs, and is associated with weight loss rather than weight gain. (Obesity is associated with the disease.)
Researchers have generally assumed that the beneficial effects of metformin are linked to its ability to prevent the liver from creating glucose from foods other than carbohydrates, which means less glucose in the blood and ultimately less deterioration of the vascular system. However, previous clinical studies of the drug suggested to Dr. Triggle and his team that a different mechanism was at work.
Using mouse cells cultivated in the laboratory, they confirmed that metformin has a direct effect on vascular function through interaction with a protein called sirtuin1, which is encoded by the SIRT1 gene known to play a role in aging. The study was also unusual in that it assessed the effects of the drug at therapeutic clinical concentrations.
"We realized some years ago that the reported and generally accepted mechanisms of metformin did not really fit with the pharmacokinetic profile — the way the drug interacts with the body," Dr. Triggle said. "Our study proves that metformin does indeed have a direct protective action on the vasculature."