Researchers at Lund University in Sweden say that patients with type 2 diabetes should be divided into subgroups and given individualized treatment. Their study “Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns, Which Associate With Future Diabetic Complications”, published in Diabetes Care, demonstrates that there are distinct epigenetic differences between different groups of patients with type 2 diabetes. The epigenetic markers are also associated with different risks of developing common complications in type 2 diabetes, such as stroke, heart attack, and kidney disease.

“We show that there are distinct epigenetic differences between subgroups of patients with type 2 diabetes. The epigenetic markers are associated with different risks of developing common complications in diabetes, such as heart attack, stroke, and kidney disease,” says Charlotte Ling, PhD, professor of diabetes and epigenetics at Lund University and lead author of the study.

“Type 2 diabetes (T2D) was recently reclassified into severe insulin deficient diabetes (SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications,” write the investigators.

“Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.

“We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6–6.1 per 1-SD increase, P < 0.01).

“Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4–1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.

“We identified differential epigenetic patterns between T2D subgroups, which associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.”

Earlier studies

A study by Lund University scientists, published in 2018, demonstrated that it is possible to divide type 1 diabetes and type 2 diabetes into five subgroups. In November 2021, the same authors published a new study which highlighted genetic differences between the four subgroups of type 2 diabetes, suggesting different causes of the disease.

The current study shows that there are also epigenetic differences between the four subgroups with type 2 diabetes. The epigenetic markers can be developed to predict common complications of type 2 diabetes, which would allow for tailored treatments of patients.

“Many patients with type 2 diabetes patients are offered standard treatments by the health care system, but growing evidence suggests that these patients need tailored treatments. Our new study adds to the evidence base that it is clinically relevant to classify patients with type 2 diabetes into subgroups to allow for more personalized treatments,” says Ling.

The new study encompasses 533 individuals recently diagnosed with type 2 diabetes from two population-based cohorts in Sweden. The authors measured DNA methylations in the blood at 800.000 sites in the genome of all participants. DNA methylation is a chemical process through which methyl groups attach to the DNA molecule, affecting the function of genes. The researchers found that the four subgroups had different levels of DNA methylation at 4.465 sites.

The findings were used to develop epigenetic risk scores to predict common complications of type 2 diabetes. Epigenetic markers associated with two of the subgroups could predict an increased risk of developing heart attack, stroke, and kidney disease.

“Heart attack and stroke are responsible for most deaths among patients with type 2 diabetes. Kidney disease causes a lot of suffering and is very costly for society, as many patients need dialysis treatment. An epigenetic biomarker that can predict complications at an early stage would make preventive actions possible,” according to Ling.

The authors will need to verify their results in other population-based cohorts. They are also planning to study DNA methylation in tissues from, for example, muscle, adipose tissue, liver, and the pancreas of the four subgroups with type 2 diabetes.

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