Blood test markers identified which can detect brain insulin resistance linked to type 2 diabetes

A research team drawn from the German Centre for Diabetes Research (DZD) with two locations in Potsdam, near Berlin, and also Tübingen, south of Stuttgart, in Baden-Württemberg has identified chemical changes to DNA in the blood that can indicate how well the brain responds to insulin. The findings suggest that a simple blood test could detect brain insulin resistance, a condition linked to obesity, type 2 diabetes (T2DM), and Alzheimer’s disease.

“Insulin is not only involved in metabolism but also plays a key role in the brain with regard to cognitive functions, appetite regulation and energy homeostasis,” said Professor Stephanie Kullmann, a researcher at the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Munich – University of Tübingen – and first author of the study. She noted that detection of brain insulin resistance has so far been costly, time-consuming and without using available biomarkers.

“Our study has shown that we can extract epigenetic signatures from the blood that very precisely indicate whether the brain is still responding to insulin or has ceased to do so,” said Professor Annette Schürmann of the German Institute of Human Nutrition Potsdam-Rehbruecke.

To identify these markers, the researchers used machine learning to analyse DNA methylation patterns – small chemical modifications to DNA – in blood samples. They examined individuals without T2DM who had similar peripheral insulin sensitivity but differed in brain insulin responsiveness. Imaging data, metabolic data and methylation profiles were integrated into the analysis.

In a cohort of 167 participants, the team identified 540 CpG sites – DNA sequences where a cytosine is followed by a guanine – with methylation patterns that distinguished between those with and without brain insulin resistance.

“It is noteworthy that many of these methylation sites were associated with an elevated risk of type 2 diabetes.

“This suggests a mutual influence between insulin resistance in the brain and metabolic disease,” said Dr Meriem Ouni of DIfE, last author of the study.

The results were replicated in two independent groups of 33 and 24 participants, achieving accuracy rates of 83 to 94 per cent, respectively. The markers proved reliable regardless of age or body mass index. For 98 of the identified CpG sites, the researchers also found a correlation between methylation in blood and brain tissue using a publicly available dataset. Many of the associated genes are involved in neuronal development, synapse formation and signal transmission.

Previous studies have shown that individuals with brain insulin resistance respond less well to lifestyle interventions, accumulate more visceral fat and experience more frequent cravings – all recognised risk factors for T2DM.

“In future, the identified epigenetic markers could serve as a screening instrument to detect at-risk individuals early and enable targeted interventions, whether through intensive lifestyle modification or novel active substances,” said Ouni.

The team now aims to develop a standardised clinical test panel based on the 540 CpG sites.

Whether such signatures can also help to identify neurodegenerative diseases, including Alzheimer’s disease, remains a subject for future research. The study was made possible through collaboration between DZD research programmes on metabolic control by the brain and on the influence of genetics and epigenetics in diabetes, with additional contributions from the University of Lübeck’s Centre of Brain, Behaviour and Metabolism and Ulm University Hospital.

For further reading please visit: 10.1126/scitranslmed.adv7834