The mystery of how the popular antidiabetic drug metformin manages blood sugar may have been solved. New research suggests that metformin affects the system of chemical markers – the epigenome – that regulates gene activity. However, pharmacoepigenetics, which studies how drugs affect the epigenome, is still in its infancy. The new discovery could therefore have significant implications for understanding the long-term effects of medications like metformin and other drugs.
Metformin is the third most frequently prescribed drug in the United States and a frontline treatment for people with diabetes worldwide – but the more than 150 million people who take metformin to help manage their blood sugar may be surprised to learn that physicians are not quite certain how it works.
“Pharmaceutical companies develop drugs, but they do not know what these drugs do,” says Charlotte Ling, a Professor of Epigenetics and Diabetes at Lund University in Sweden. “They study the outcome they consider important” – the therapeutic effect – but how they work is often left behind.
New research, published in June in Diabetes Research and Clinical Practice, suggests a potential mechanism for metformin.
After studying blood and tissue samples from hundreds of people newly diagnosed with diabetes, scientists conclude that metformin affects the epigenome – a system of chemical markers that acts as a dimmer switch on your genes, boosting some and downregulating others without changing the DNA itself.
And since epigenetic changes can be long-lasting – and potentially even passed on to children –understanding the role of medications like metformin in shaping the epigenome is vital, the authors say.
Nurture rules
Your DNA is wound around proteins called histones like thread on a spool – the tighter a certain region is wound on its histone, the more difficult reading that stretch of DNA is and the lower the activity of any genes located there. Other chemical flags to your DNA can suppress or supercharge the activity of genes by blocking or attracting transcription proteins. Epigenetics studies how your lived experience can modulate gene activity through this level of genetics over DNA, explains Sonia García-Calzón, an Assistant Professor at the University of Navarra in Pamplona, Spain and lead author.
“You cannot modify your genetics,” says García-Calzón. “But your epigenome can be modified by what you eat, by how much exercise you take or by medicine.”
Scientists have tied certain experiences – such as hunger or trauma in childhood – to epigenetic changes that persist into adulthood and are tied to certain conditions, including heart disease and diabetes.
Although such factors as stress, pollution exposure and substance use are frequently studied in epigenetics, scientists have only recently begun to consider epigenetics as a potential mechanism of action for medicines, Ling says.
Previous research by Ling and García-Calzón identified epigenetic effects from statins, cholesterol-lowering drugs that are the most widely prescribed medication in the world. But could epigenetics help explain the mystery of why metformin works?
Blood sugar and chemical sticky notes
To determine how metformin might affect the epigenome, García-Calzón and her team analysed blood samples from hundreds of people newly diagnosed with diabetes in southern Sweden – 92 of whom had started metformin treatment and 230 who had not.
The researchers used special sequencing tools to scan for evidence of changes to the epigenome. One telltale sign is methylation, a chemical sticky note of the epigenome that flags a specific gene for special treatment. Depending on its placement within a gene, methylation can promote transcription or downregulate it.
After examining 850,000 sites in the genome – “which is actually very few, about 3–4% of the total methylation marks,” García-Calzón says – the team identified 26 sites at which methylation differed between those receiving metformin and those who did not.
Four of the genes with methylations have previously been associated with diabetes, García-Calzón says. But were the epigenetic changes a side-effect of the metformin treatment or the mechanism behind its therapeutic properties?
García-Calzón’s team examined the methylation patterns of each of the people receiving metformin and compared them with their glycosylated haemoglobin (HbA1c) levels – a measure of their long-term blood sugar that indicates how well they respond to the metformin treatment.
Statistical analysis revealed that variation at just three methylation sites accounted for 32% of the effect of metformin on HbA1c. The authors say that this is compelling evidence that methylation is at least one cause of metformin’s antidiabetic effects.
Next, the researchers determined whether the methylation patterns in the blood were reflected in key tissues in diabetes – adipose tissue, the body’s energy stores; skeletal muscle, an important consumer of glucose; and the pancreatic islets, where insulin is produced.
Two of the 26 methylation sites identified in blood were also methylated in skeletal muscle and adipose tissue. And in the pancreatic islets, evidence indicated that methylation affected gene activity – several genes that had been methylated among those taking metformin were expressed differently among the people taking metformin than controls.
Washout time and future studies
Metformin seems to affect the epigenome strikingly fast, Ling says – the average participant had been taking metformin for only 3 months, and some had started just 1 week before. People who have taken metformin for years could have even more dramatic epigenetic differences, especially since metformin is prescribed for long-term use.
A natural question – for metformin and other medicines that affect the epigenome – is whether the changes persist after you stop taking the drug. There is little or no information on the washout time for drug-induced epigenetic changes, Ling says, but studies with other kinds of interventions suggest that even brief exposure can be hard to shrug off.
“I was involved in an epigenetic analysis in which my collaborator in Copenhagen exposed young healthy men to 5 days of a high-fat diet,” she says. Even after their diets returned to normal, “washing out these epigenetic changes actually turned out to be difficult.”
“Environmental insults seem to be able to introduce epigenetic changes that may be difficult to reverse,” she adds.
Now, Ling’s team has pivoted to studying epigenetics in an environment with fewer variables – “we take human tissues in culture and expose them to drugs,” Ling explains. She says this set-up gives researchers more control – and the luxury of continued access over time.
The field of pharmacoepigenetics – the study of how drugs affect the epigenome – is in its infancy but is here to stay. “This is definitely not studied enough,” says Ling. “It needs to be investigated further.”
