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DNA Does Not Forget

Jan 12, 2021
Editor: Steve Freed, R.PH., CDE

Author: Brianna Belton, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences

Because of metabolic memory, complications of poor glucose control may not be reversed and will continue to progress even after glucose levels are normalized. 

Prolonged hyperglycemia can lead to numerous complications affecting the eyes, kidneys, nervous system, and cardiovascular system. Even if blood glucose levels are reduced, the effects can be permanent, potentially leading to further complications. This is known as metabolic memory and explains the importance of controlling blood glucose levels sooner rather than later. For example, if hyperglycemia persists long enough that the patient develops retinopathy, the retinopathy will continue to progress even when the blood glucose levels are normalized. 


In the Diabetes Control and Complications Trial (DCCT), researchers had the goal of determining the effect of intensive treatment to manage blood glucose concentrations close to normal ranges on the frequency and severity of long-term complications of diabetes in patients with type 1 diabetes. For about 6.5 years, complications were assessed regularly. Intense treatment was defined as three or more doses of insulin per day by injection or by the use of an insulin pump with blood glucose monitoring at least four times per day. These patients met with their health care team every month. Patients treated with intensive diabetes treatment were compared to patients treated with conventional medicine, including one or two insulin shots per day with daily glucose monitoring of urine or blood glucose. These patients met with their health care team every three months.  

The DCCT trial demonstrated that patients with type 1 diabetes with blood glucose levels kept as close to normal as possible with intensive treatment had fewer diabetes-related health problems than conventional therapy patients. Patients treated with intensive treatment had an A1C of about 7%, while patients with traditional treatment had an A1c of about 9%. An intensive treatment that was early and aggressive has decreased the risk of eye disease, kidney disease, and nerve disease, all by at least 50%. The risk of eye disease was reduced by 76%, kidney disease by 50%, and neuropathy by 60%. Although patients receiving intensive treatment had decreased risk of complications, there was a higher risk for hypoglycemia. 

As an observational follow-up to the DCCT, the ongoing Epidemiology of Diabetes Interventions and Complications (EDIC) study was established to follow the DCCT participants for the past 20 years. Researchers wanted to determine how diabetes affects the body over time. EDIC demonstrates the long-term benefits of early intensive treatment for blood glucose control on diabetes-related complications, such as retinopathy; it has also been shown to lengthen life. Furthermore, it showed that regular eye exams ultimately reduced the costs and frequency of eye exams and led to earlier diagnosis and diabetes-related eye disease treatment. Results showed that the intensive treatment provided during the DCCT study lowered the risk of CVD by 57%, eye surgery by 48%, kidney disease and failure by 50%, and neuropathy by 30%. 

The involvement of epigenetics in metabolic memory was also investigated in the DNA of 499 randomly selected DCCT participants who were also followed up in the EDIC study. The type of epigenetic modification that was studied is DNA methylation. Methylation turns off genes preventing the production of proteins that they are supposed to encode. Researchers looked for associations between controlled blood glucose levels, DNA methylation, and the development of diabetes-related complications. The epigenetic changes can explain 68-97% of the complications presented during the EDIC study. 

The DCCT and EDIC studies were used to describe metabolic memory. These trials successfully described the relationship between glycemic control and reduced long-term complications. According to the National Institute of Diabetes and Digestive and Kidney Diseases, these studies’ results have changed how diabetes is managed worldwide. Early and intensive blood glucose control is now the standard treatment for those with type 1 and type 2 diabetes to allow patients to live longer lives with reduced risk of debilitating complications.  

Practice Pearls 

  • Metabolic memory describes the prolonged effects of uncontrolled diabetes. Without early and aggressive methods to get blood glucose levels as close to normal as possible, permanent changes will continue to persist even after glycemic control has been established. 
  • DCCT and EDIC demonstrate how early and adequate diabetes treatment can significantly reduce the risks of long-term complications. 
  • A specific epigenetic mechanism, DNA methylation, appears to mediate the association between uncontrolled hyperglycemia, diabetes-related complications, and metabolic memory. 


Blood Glucose Control Studies for Type 1 Diabetes: DCCT and EDIC. (, 2020). Retrieved July 27, 2020 

Chen, Z., Miao, F., Braffett, B. H., Lachin, J. M., Zhang, L., Wu, X., Natarajan, R. (2020). DNA methylation mediates the development of HbA1c-associated complications in type 1 diabetes. Nature Metabolism. doi:10.1038/s42255-020-0231-8 


Brianna Belton, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences