Decoding “metabolic memory” – how do glycemic control and variability affect epigenetic changes in young people with type 1 diabetes?

Type 1 diabetes (T1D) is the most common metabolic disease in childhood. It is caused by the destruction of pancreatic beta cells by one’s malfunctioning immune system. The lost beta cells are responsible for the production of insulin – an essential hormone in blood glucose levels regulation. Treatment of T1D demands life-long subcutaneous insulin supplementation to control blood glucose levels close to those observed in healthy peers and thus circumvent the development of severe, long-term complications. However, not only treatment intensity but also its timing are critical for the development of long-term complications. Extensive clinical trials reported that better glycemic control in the first years after diabetes diagnosis was associated with a lower risk of complications development, the effect which persisted for over 16 years after the trial’s completion despite the diminished difference in blood glucose levels on follow-up. This phenomenon, dubbed “metabolic memory”, is the focus of this project.

A possible explanation of metabolic memory is connected with epigenetic modifications of human DNA. These modifications affect how the genetic code (DNA) is “understood” and acted upon by the different cells in our organism. Thus, even though all cells possess the same DNA data, epigenetic changes modify the availability of its fragments and activate or suppress the production of specific proteins. Early exposure to high glucose was associated with epigenetic changes that could persist, resulting in altered cell function and increasing the future risk of complications.

In this project, we aim to investigate how the DNA methylation pattern (which fragments are methylated and how much) changes during the first years of type 1 diabetes treatment. To do so, we plan to recruit children and young adults aged 7- 16 with confirmed type 1 diabetes duration for 12 to 24 months. We plan to focus primarily on patients with poor glycemic control and to evaluate the changes due to their clinical improvement within the next 12 months. The prospective observation of patients will allow us to inspect if the observed methylation patterns associated with increased risk of complications may be reversed or exacerbated in patients that don’t improve or worsen their glycemic control.

All participants will be monitored using the continuous glucose monitoring (CGM) systems, allowing for glucose measurement with unprecedented resolution, better assessment of glucose exposure and clinical improvement than with methods available in the past. Genetic material will be isolated from blood samples drawn at the beginning and on follow-up observations (3, 6, 9 and 12 months), and the DNA methylation patterns will be measured. Additionally, expression of few selected proteins associated with diabetes complications will be measured on samples from the subset of patients with the most defined changes in DNA methylation and glycemic control. Direct data from protein expression will confirm if observed methylation patterns directly alter genetic material availability and modulate cell functions.

The results of this project will allow us to better understand the mechanisms and dynamics of metabolic memory formation and identify how this process can be modulated by treatment and glycemic variability.

The projects is funded under PRELUDIUM BIS 4 NCN call. Read more about the project here.

Decoding “metabolic memory” – how do glycemic control and variability affect epigenetic changes in young people with type 1 diabetes?
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