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Epigenetic Markers Predict Type 2 Diabetes Patients Who Respond to, Tolerate Metformin

NEW YORK – Epigenetic markers can distinguish between individuals with type 2 diabetes who respond to metformin treatment and those who do not, a new study has found. 

Metformin is commonly prescribed to individuals with type 2 diabetes, but about 30 percent of patients don't respond to the drug and between 20 percent and 30 percent experience side effects that can be intolerable.

As part of the All New Diabetics In Scandia (ANDIS) study, researchers led by Lund University's Charlotte Ling conducted a pharmacoepigenetic study to gauge whether epigenetic markers could be used to predict drug response and tolerance among type 2 diabetes patients (T2D).

After uncovering sites where DNA methylation differed between the groups, the researchers developed two methylation risk scores that could predict which patients would or would not respond to treatment and would or would not experience side effects. 

"This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy," Ling and her colleagues added in their paper, which appeared Thursday in Science Translational Medicine.

The researchers conducted multiple epigenome-wide association studies by analyzing blood samples collected from the ANDIS cohort using Illumina's MethylationEpic array. They in particular sought to gauge whether differences in DNA methylation prior to treatment could predict whether individuals had changes in glycated hemoglobin, responded to the drug treatment, or experienced intolerance to the drug following about a year and a half of metformin treatment.

Within the discovery cohort, the researchers identified more than 2,500 methylation sites that were significantly associated with changes in glycated hemoglobin, a marker of blood glucose levels. In the replication cohort, 132 CpGs of these sites were validated. 

They additionally uncovered 7,916 methylation sites that differed between individuals with T2D who responded to metformin and individuals who did not. Of those, 601 were then validated in the ANDIS replication cohort and 329 in an additional ANDiU and OPTIMED replication cohort

In all, 33 CpG sites were associated with future metformin response in all cohorts, and in a combined meta-analysis 11 sites reached genome-wide significance.

At the same time, the researchers found 9,676 methylation sites that differed between individuals with T2D who could tolerate metformin treatment and those who could not. 

In the ANDIS replication cohort, 235 CpGs were validated, and in the ANDiU and OPTIMED replication cohort, 352 CpGs were. Seven CpGs were associated with metformin in all cohorts, and in a combined meta-analysis four sites reached genome-wide significance. 

Following this, the researchers generated two methylation risk scores, one of metformin response and one of metformin intolerance. For the metformin response, they bundled together the 11 sites to form a weighted methylation risk score that could differentiate between responders and non-responders with an area under the curve of between 0.80 and 0.89.

Meanwhile, for metformin intolerance, they combined the four sites that reached genome-wide significance into a separate risk score that could differentiate between tolerant and intolerant individuals with an area under the curve of between 0.85 and 0.94.

These findings indicated to the researchers that their epigenetic markers might be able to stratify non-responsive and intolerant patients when they are diagnosed with T2D. "Such stratification may help patients with T2D receive an optimal therapy and could be a step toward personalized medicine," Ling and her colleagues wrote.

Additionally, in a series of functional analyses, the researchers found that some of the genes associated with these epigenetic changes appear to have T2D-relevant roles. For instance, silencing four of the genes implicated in metformin response or tolerance through the epigenome-wide study led to the altered expression of metformin transporters and enzymes involved in gluconeogenesis. This suggested the epigenetic markers could regulate gene transcription. 

"Overall, we shed light on some potential biological mechanisms related to our epigenetic markers and their link to metformin response or intolerance," the researchers added.