Researchers at the University of Toronto have recently discovered the mechanism of action for two well-studied molecules critical to the treatment of diabetes and obesity: metformin and resveratrol. Metformin is a commonly prescribed drug for the treatment of Type 2 diabetes, while resveratrol is a molecule commonly found in red wine and blueberries. Although these molecules have been under investigation for some time, their effects in the body at the cellular level have remained elusive.
Now, thanks to work from Dr. Tony Lam’s lab at the Toronto General Research Institute, this is no longer the case. The two studies from Dr. Lam’s lab, published in Nature Medicine, describe the role of AMP-activated protein kinase (AMPK) and NAD+-dependent deacetylase sirtuin 1 (SIRT1) in the pathways of metformin and resveratrol, respectively. Essentially, AMPK is a regulator of metabolism that functions by adding the phosphate groups onto molecules. Similarly, SIRT1 functions to control gene expression by removing chemical groups known as “acetyls” and has been associated with insulin sensitivity.
Initially, the team focused on SIRT1 in the small intestine of rat models, as this is the location where resveratrol levels remain the highest after ingestion. To study SIRT1, the authors chose to use a method of gene silencing to see what happens when the protein is not present in cells. This gene silencing involved mRNA, which is the code produced from DNA that dictates which proteins are formed in a cell. One method of removing, or silencing, a protein is to destroy its corresponding mRNA so that the cell can no longer make the protein. To achieve this effect in the rat models, the authors injected a lentivirus containing a small hairpin RNA (shRNA). This shRNA was complementary to the mRNA of SIRT1, which resulted in the silencing of the gene. The rats with the SIRT1 gene knockdown showed induced hepatic insulin resistance. Through this result, the authors demonstrated that SIRT1 increases insulin sensitivity in the liver, and that activation of SIRT1 could be a valid therapeutic target. Furthermore, the authors went on to demonstrate that resveratrol succeeds in activating a gut-brain-liver neural pathway leading to decreased hepatic glucose production.
Using similar techniques involving rat models, the researchers also discovered that the pathway for metformin relies on an AMPK mechanism. When AMPK is inhibited, the effects of metformin are not as pronounced.
Together, these results elucidate a previously unknown pathway regarding metabolism regulation, and one that could be crucial for developing future therapeutic options for people with obesity and diabetes. Metformin has even been shown to have various other effects, including the ability to stimulate neurogenesis (the growth of new neurons) in mouse models. This work, done by Dr. Frieda Miller and colleagues at the University of Toronto, elucidates the robust medical applications of metformin for both diabetes and nervous system therapy.
Although the application of these molecules seems very promising, there are many barriers to overcome before they can be widely used. Resveratrol has been shown to have poor success in humans, due to poor bioavailability in peripheral tissues. Despite many common myths, that late night glass of wine might not be so medically relevant after all, in the case of resveratrol at least. However, thanks to Dr. Lam’s and Dr. Miller’s groups, the future is optimistic for therapies regarding diabetes, obesity, and even nervous system diseases.
