Epigenetic Study Reveals Novel Subgroups for Type 2 Diabetes

Today over 400 million people around the globe are living with diabetes, the more significant majority of which have type 2. In all cases, the disease disrupts the body’s use of glucose, making it difficult for cells to take in needed sugar from the blood. Over time, high blood sugar levels can lead to problems with the kidneys, nerves, eyes, and feet, as well as comorbidities like heart disease and stroke.

Diabetes is a chronic condition, meaning that people who have it must learn to live with it for the rest of their lives. Medication and lifestyle management are a must. Yet, not all treatments work for everyone. It has been suggested by some in the field that diabetes may be more varied than we know, just like cancer and other diseases. Looking specifically at Type 2 diabetes (T2D), researchers have suspected differences for some time. However, not until recently, with the advance of modern technologies, has there been any evidence of this. 

A new study from Lund University (LU) in Sweden has found that T2D should be separated into subgroups, allowing for more individualized and targeted treatment options. The differences were identified by examining the epigenetic marks found in the blood of patients with T2D. As reported in the journal of Diabetes Care, the study has reclassified the disease based on sub-group unique DNA methylation patterns.

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

Previous studies have demonstrated roles for various epigenetic mechanisms in the development of T2D, including histone modifications, non-coding RNAs, and DNA methylation. Epigenetic modifications are heritable changes in gene expression that can be influenced by similar environmental factors that heighten the risk for T2D, such as lifestyle and diet. 

In a renowned 2018 study, the Lund researchers demonstrated that type 1 and type 2 diabetes could be distinguished into five secondary groups. Three years later, the same research team found genetic differences among the four subgroups of T2D, indicating that the diseases may have distinct origins or underlying molecular mechanisms. 

In the current study, the team investigated the same four T2D subgroups, reported as 1) severe insulin-deficient diabetes (SIDD); 2) severe insulin-resistant diabetes (SIRD); mild obesity-related diabetes (MOD); and 4) mild age-related diabetes (MARD).

Using genome-wide DNA methylation analysis, they investigated whether DNA methylation differed among the subgroups and whether a methylation risk score (MRS) associated with each group might predict diabetic complications. 

“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,” said Ling.

The study investigated over 500 blood samples supplied from 2 cohorts of people recently diagnosed with T2D. After analyzing DNA methylation at 800,000 sites along the genome, the study found distinct differences at 4.465 sites among the 4 subgroups.

Their data verified that the subgroups did indeed have epigenetic differences and that an MRS risk valuation test could be applied to predict future health consequences. Thus, the results support the notion of reclassifying diabetes into subgroups so patients can be treated with more precision therapies rather than as a whole.

“Many patients with type 2 diabetes are offered standard treatments by the health care system, but growing evidence suggests that these patients need tailored treatments,” says Ling. “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.”

The team hopes to use their findings to develop epigenetic risk score assessments that can predict diabetic complications. For example, two subgroups had epigenetic markers associated with the risk for heart attack, stroke, and kidney disease.

Although more research is needed to verify the results found here, the Lund group plans to investigate DNA methylation in various tissues in four T2D subgroups. They anticipate seeing similar epigenetic differences in the subjects’ liver, pancreas muscle, and adipose tissue.

Source: S. Schrader, et al. Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns, Which Associate With Future Diabetic Complications. Diabetes Care, 2022.

Reference: Epigenetic markers predict complications in patients with type 2 diabetes. Lund University, May 25, 2022.

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