Researchers at the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) and the German Center for Diabetes Research (DZD) have gained new insights into the molecular adaptations in skeletal muscle after bariatric surgery in obese patients with and without type 2 diabetes. They have published their findings in the journal “Diabetes & Metabolism.”

Bariatric surgery is a widely recognized intervention for the treatment of obesity. In this medical procedure, changes are made to the stomach, intestines or both organs with the aim of significantly and sustainably reducing body weight. Bariatric surgery is used in particular when diet and lifestyle interventions have not achieved long-term weight loss.

It is known that during the development of type 2 diabetes, epigenetic changes (DNA methylation and hydroxymethylation) occur in skeletal muscle, the tissue that plays the most important role in insulin-stimulated glucose uptake. However, the extent to which these changes can be reversed by interventions such as bariatric surgery has been unclear so far.

Clinical results linked to the transcriptome and epigenome

An interdisciplinary DZD team, including Leona Kovac, Annette Schürmann and Meriem Ouni from the DIfE and Sabine Kahl and Michael Roden from the German Diabetes Center (DDZ), therefore used a comprehensive bioinformatics approach to investigate the effects of surgically induced weight loss on metabolic, transcriptional and epigenetic adaptations in the skeletal muscle of obese patients with and without type 2 diabetes.

In addition, multidimensional relationships between the molecular and metabolic changes induced by bariatric surgery were analyzed to identify new prominent candidate genes associated with weight loss and muscle function.

The subjects were participants in the BARIA-DDZ study, a prospective cohort study, which comprehensively characterizes the metabolism of obese patients before and up to five years after bariatric surgery. The study described here focused on the metabolic and molecular results that were achieved in the first year after surgery in 13 men with obesity and 13 men with obesity and type 2 diabetes. Both groups underwent anthropometric and metabolic examinations before and one year after the operation, including taking a muscle biopsy and measuring tissue-specific insulin sensitivity.

Impaired epigenetic flexibility

The DZD researchers observed different molecular reactions in skeletal muscle one year after bariatric surgery. Before the operation, the obese diabetes patients showed higher fasting glucose and insulin levels and lower insulin sensitivity compared to the obese participants without type 2 diabetes. After the operation, the improved metabolic status was more pronounced in the obese participants without type 2 diabetes. This was reflected in differential gene expression patterns related to insulin signaling pathways, intracellular signal transduction and oxidative phosphorylation. In contrast, the obese diabetes patients showed changes only in genes that are associated with ribosome and spliceosome functions and were accompanied by fewer changes in DNA methylation. This might be due to the altered expression of a type 2 diabetes risk gene that is involved in demethylation processes.

Tailored individual therapies

The findings underline the importance of molecular adaptations in skeletal muscle after bariatric surgery, especially in people with type 2 diabetes. “Our study suggests that epigenetic mechanisms play a crucial role in mediating these responses and predicting health status,” says Dr. Meriem Ouni.

“Our future research will investigate the molecular mechanisms underlying the changes in DNA hydroxymethylation and their potential postoperative function in skeletal muscle. In addition, we intend to test specific target structures identified by the bioinformatics approach as potential therapeutic targets in muscle," added Prof. Dr. Annette Schürmann, head of the Department of Experimental Diabetology at the DIfE. For example, therapeutic approaches might be tailored to people with different metabolic profiles.

Funding

The collaboration between the DDZ and the DIfE was supported by a grant from the DZD and underlines the importance of multidisciplinary research in the management of complex metabolic disorders.

Original publication
Kovac, L., Gancheva, S., Jähnert, M., Sehgal, R., Mastrototaro, L., Schlensak, M., Granderath, F. A., Rittig, K., Roden, M., Schürmann, A., Kahl, S., Ouni, M.: Different effects of bariatric surgery on epigenetic plasticity in skeletal muscle of individuals with and without type 2 diabetes. Diabetes Metab. 50 (5) (2024) [Open Access]

Related publications
Ouni, M., Kovac, L., Gancheva, S., Jähnert, M., Zuljan, E., Gottmann, P., Kahl, S., de Angelis, M. H., Roden, M., Schürmann, A.: Novel markers and networks related to restored skeletal muscle transcriptome after bariatric surgery. Obesity 32(2), 363-375 (2024). [Open Access]

Gancheva, S., Ouni, M., Jelenik, T., Koliaki, C., Szendroedi, J., Toledo, F. G. S., Markgraf, D. F., Pesta, D. H., Mastrototaro, L., De Filippo, E., Herder, C., Jähnert, M., Weiss, J., Strassburger, K., Schlensak, M., Schürmann, A., Roden, M.: Dynamic changes of muscle insulin sensitivity after metabolic surgery. Nat. Commun. 10(1):4179 (2019). [Open Access]

Background information
Epigenetics investigates those properties of genes that do not manifest themselves through changes in the DNA sequence itself, but through their readiness to be read. Epigenetic information is mediated by methyl groups or other biomolecules (methylation and hydroxymethylation) which, like chemical locks, deny or allow access to certain DNA sequences and thus control their activability. They act like a kind of switch in the genome that turns a gene on or off. Epigenetic changes can be triggered by lifestyle and, according to the current study, also by surgically induced weight loss.

Scientific contact
Dr. Meriem Ouni
Research associate in the Department of Experimental Diabetology
Phone: +49 33200 88-2505
E-Mail: meriem.ouni(at)dife.de

Prof. Dr. Annette Schürmann
Head of the Department of Experimental Diabetology
Phone: +49 33200 88-2328
E-Mail: schuermann(at)dife.de

Press contact
Public relations DIfE
Phone: +49 (0)33 200 88 - 2335
E-Mail: presse(at)dife.de
 

German Institute of Human Nutrition Potsdam-Rehbruecke 
The DIfE is a member of the Leibniz Association. It investigates the causes of diet-related diseases in order to develop new strategies for prevention and therapy and to provide dietary recommendations. Its research focus includes the causes and consequences of the metabolic syndrome, which is a combination of obesity, high blood pressure, insulin resistance and lipid metabolism disorder, as well as the role of diet in healthy aging and the biological basis of food choices and eating habits. www.dife.de/en

The German Center for Diabetes Research (DZD) is one of eight German Centers for Health Research. It brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. www.dzd-ev.de/en