Dr Chris Triggle (left), Dr Gnanapragasam Arunachalam (centre) and Dr Hong Ding who studied Metformin.
DOHA: Researchers at Weill Cornell Medical College in Qatar (WCMC-Q) have shed light on the molecular and cellular mechanisms of one of the drugs widely used for diabetes, which has been poorly understood for more than 50 years.
Experiments by WCMC-Q’s Dr Chris Triggle in the laboratory demonstrate that Metformin, the first-choice hypoglycemic drug prescribed to most type-2 diabetics, interacts with the so-called ‘longevity gene’ SIRT1 to protect the user’s vascular system against deterioration caused by glucose toxicity.
Postdoctoral fellow and lead author of the project, Dr Gnanapragasam Arunachalam, worked with Dr Triggle, Professor of Pharmacology, and Dr Hong Ding, Assistant Research Professor of Pharmacology, to produce the study, published online in the British Journal of Pharmacology.
Dr Triggle, who is the lead principal investigator of a Qatar Foundation-sponsored National Priorities Research Programme project exploring effects of diabetes on the vascular system, said Metformin had long been known to reduce morbidity in patients with diabetes-associated microvascular disease, but until now the reason for this beneficial effect had not been understood.
“Metformin is a very interesting drug that was first introduced in 1958 in the UK for the treatment of type-2 diabetes.
“It is comparatively free of significant side effects and unlike most other oral hypoglycaemic drugs, it lacks a significant risk of producing hypoglycaemia, which can increase cardiovascular risk.
“The use of Metformin is associated with weight loss rather than weight gain — an obvious benefit when many with type-2 diabetes are overweight.
“The most common cause of death among diabetes patients is vascular and microvascular deterioration — it’s like an advanced aging of the vascular system — so Metformin is an extremely useful drug.”
He said that it had generally been assumed that beneficial effects of Metformin are linked to its ability to inhibit hepatic gluconeogenesis (generation of glucose from non-carbohydrate sources by the liver), which means less glucose in the blood and therefore less vascular deterioration.
However, analysis of data from clinical studies of the drug gave Dr Triggle and his team cause to believe a different mechanism was at work.
“We realised 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 — of the drug. Our study proves that Metformin does indeed have a direct protective action on the vasculature.”
Experiments on cultivated mouse cells in the laboratory confirmed that Metformin has a direct effect on the vascular function through interaction with a protein called sirtuin 1, which is encoded by the SIRT1 gene, known to play a role in aging.
The study is also unusual in that it assessed effects of the drug at therapeutic clinical concentrations.