Wednesday, July 5, 2017

Another reason to continue Metformin for your type II diabetes !!

Fragile X syndrome is a genetic disease caused by defects in the Fragile X Mental Retardation 1 gene (FMR1), which triggers excess production of protein in the brain, as well as dysregulated connections between neurons and changes in behavior. The condition leads to impairments in speech and language, behavior and social interaction. It affects about 1 in 5,000 boys and 1 in 6,000 girls and is often co-diagnosed with autism, anxiety disorders and seizures. I have never personally worked on the Fragile X syndrome but I have indirectly been associated with ongoing research efforts about this disease through a close friend of mine and an accomplished neuroscientist Dr. Udai Bhan Pandey, currently an associate professor of Human Genetics at University of Pittsburgh. Earlier in his career, Dr. Pandey worked on Fragile X syndrome for his Ph.D. dissertation in the same lab in which I was working on a GI cancer model.  I vividly remember how passionately he used to talk about this disease and as to how there is no cure for fragile X syndrome back in 2003. Even today after 14 years, there is no cure yet.

A new study led by researchers at McGill University, the University of Edinburgh and Université de Montréal has found that Metformin improves social, behavioral and morphological defects in mice model of Fragile X syndrome. For those who are not aware about Metformin, it is a common drug used in individuals with high risk for diabetes type 2, obesity or impaired glucose tolerance. It has had a strong safety profile in children and adults with type 2 diabetes and obesity. 

Ilse Gantois, Arkady Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Erika Freemantle, Ruifeng Cao, Vijendra Sharma, Tine Pooters, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong, Shane Wiebe, Isabelle A Groves, Seyed Mehdi Jafarnejad, Clément Chapat, Elizabeth A McCullagh, Karine Gamache, Karim Nader, Jean-Claude Lacaille, Christos G Gkogkas, Nahum Sonenberg. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nature Medicine, 2017; DOI: 10.1038/nm.4335

In this study, Gantois et al. beautifully demonstrate that metformin, a type II diabetes drug that crosses the blood-brain barrier, corrects various neurological and behavioral phenotypes of fragile x syndrome in a mouse model known as Fmr1−/y.  These mice have increased abundance of an kinase (a type of cellular enzyme) known as RAF and enhanced activity of its related kinases and gene targets. These investigators found that a chronic (10-day) treatment with metformin reduced the abundance of RAF and suppressed the activation of enzymes such as MEK, ERK, mTOR, and translation initiation factor eIF4E in the prefrontal cortex and hippocampus of Fmr1−/y mice which are important molecules in the pathogenesis of fragile X disease. Decreased mTOR activity correlates with decreased expression of the gene encoding MMP9, a protease (another type of enzyme) that regulates synaptic function. Metformin suppressed repetitive behavior, the incidence of macroorchidism, and defects in dendritic spine development and synaptic activity in Fmr1−/y mice, phenotypes that are common in fragile x syndrome patients.

Please note that this study is conducted in mice model, and in spite of lot of similarities between mice and human, further tests will be needed to assess whether metformin can specifically improve cognitive function in mammals and assess the extent of its benefits versus its side effects which are many. Yet scientific community is very optimistic about these findings suggesting that metformin might be repurposed for use in fragile x patients.

Dr. Nahum Sonenberg, a pioneering scientist of our times, best known for his seminal contributions to our understanding of translation of proteins from RNAs, and notable for the discovery of the mRNA 5' cap-binding protein, eIF4E, the rate-limiting component of the eukaryotic translation apparatus and also a senior author of this research work says about Metformin:  "Basically, it's something like a wonder drug,"

'Wonder drug' in the past few years, metformin has generated extensive interest for its potential in treating numerous health problems such as cancer, cardiovascular diseases, neurological diseases and aging. Numerous preclinical, epidemiological and clinical studies in the past have suggested that metformin use is associated with inhibition of cancer cell growth and reduction in all-cancer incidents in comparison with users of other hypoglycemic drugs. So if you are type 2 diabetes patient and your doctor has advised you to take metformin, you have another good reason to keep taking this drug regularly without fail.

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