Metformin is often described as the first-line medication for the treatment of type 2 diabetes. However, not all patients respond to the drug. Researchers at Lund University have discovered a combination of biomarkers that can predict which patients will benefit from the treatment. This work is now continuing in order to confirm the results in a larger patient group, with the intention of developing a test for clinical use.
The drug metformin has been in use for decades to treat type 2 diabetes. Metformin lowers blood sugar levels in patients and reduces the risk of developing complications of diabetes. However, not all patients respond to this treatment and therefore risk elevated blood sugar levels. Some patients also experience side-effects from metformin, such as stomach complaints.
"Many patients who experience side-effects suffer in silence and quite unnecessarily. It is important to tell your doctor, as there are other drugs available," says Mats Martinell, medical doctor and member of Excellence of Diabetes Research in Sweden (EXODIAB), one of Lund University's strategic research areas.
Enormous response
A research project is currently underway at Lund University to discover which patients will benefit from metformin treatment and which should receive an alternative drug. The research has resulted in the discovery of a combination of biomarkers that, with a blood test, can predict which individuals with type 2 diabetes will benefit from the drug and which are likely to suffer side-effects. The study was published last year in the September issue of the journal Science Translational Medicine.
"I have received an enormous response and many people with type 2 diabetes have written to me. In fact, during the summer an elderly man knocked on the door of my summer house. He had googled experts and found my name. He had type 2 diabetes and was prescribed metformin, but the drug was making him unwell and he wondered what he should do," says Charlotte Ling, professor of epigenetics at Lund University and one of the lead authors of the study.
Detecting epigenetic patterns
The study is based on three population studies: All New Diabetics in Skåne (ANDIS), All New Diabetics in Uppsala (ANDiU) and the Latvian study Optimized Program of Personalized Treatment of Type 2 Diabetes (OPTIMED). The study encompassed 363 individuals recently diagnosed with type 2 diabetes. Researchers tested the blood sugar levels of all participants prior to first taking metformin and again 18 months later. While the treatment had a clearly positive effect on 121 people, blood sugar levels did not decrease in 91 individuals. By measuring DNA methylation in the blood cells of participants, the researchers were able to identify an epigenetic pattern that served as a type of biomarker. DNA methylation is a chemical process that controls gene function.
"We found a combination of biomarkers that provided good separation between the group that responded well to metformin treatment and those that did not respond well," says Charlotte Ling.
Inter-university collaboration
Mats Martinell is an associate professor and senior lecturer in general medicine at Uppsala University and project manager of ANDiU. He is also co-author of the study published in Science Translational Medicine.
"I am delighted that our population study of Uppsala proved helpful to our colleagues at Lund University. We need to collect samples from participants in various geographical areas in order to develop the necessary knowledge. Modern research is not conducted in a single researcher's laboratory but in inter-university collaborations. Access to population studies is crucial if we are to validate our results. This is the linchpin of any scientific methodology," says Mats Martinell.
Support for the research project
Many type 2 diabetes patients have asked Charlotte Ling if a test is already available to check whether metformin will help them. Although professor Ling has submitted a patent application for her discovery, much work remains to be done before a product is ready for the market. First, the researchers need to verify their results in other, larger patient groups.
"We are currently searching high and low for patient cohorts that we can use to validate our results. This presents something of a challenge, as we need patients who have given blood samples before being prescribed metformin. In the long term, my hope is that this research can contribute to the development of a test kit that healthcare professionals can use to check who will benefit from the treatment," says Charlotte Ling, who was recently awarded a grant of approximately SEK 700,000 by the European Foundation for the Study of Diabetes (EFSD) and the Novo Nordisk Foundation for her research project in the field of precision medicine.
Mats Martinell sees a significant need for innovation in the care and treatment of patients with type 2 diabetes.
"Any product that reduces the patient's suffering and makes it easier for the health service to provide personalised care and treatment is valuable. It would be tremendous if this research could contribute to reducing the cost of healthcare," he says.
Facts about epigenetics and DNA methylation
Epigenetic changes occur when environmental or behavioural factors cause functional changes to the genome, the complete set of DNA contained in our cells. Our genes are inherited and cannot be changed. DNA methylation, one of the mechanisms that cause epigenetic changes, is a chemical process through which methyl groups attach to the DNA molecule, affecting the function of genes.
When the first studies of epigenetics and type 2 diabetes were conducted over a decade ago, DNA methylation was analysed on selected candidate genes, or small segments of the genome. Technological advances made it possible to analyse the entire genome down to its smallest constituents, where methylation takes place.
Today, we can use a technique called whole-genome bisulfite sequencing (WGBS) to study the epigenome, all of the many chemical compounds that regulate gene expression, which in addition to DNA methylation also includes various histone modifications and small non-coding RNAs.
