Several years ago, DZD researchers were able to classify individuals with a risk of type 2 diabetes into six clearly distinguishable risk clusters that differ significantly in diabetes incidence, and the progression of diabetes-related complications.* Among these, clusters 3 and 5 show a particularly high risk of developing type 2 diabetes. In the current analysis, the research team investigated whether the effectiveness of prevention of diabetes also differs between risk groups in the context of sustained long-term weight loss.
Individuals in Cluster 5 Remain at High Diabetes Risk Despite Lifestyle Changes
The study was based on data from the Tübingen Lifestyle Intervention Program (TULIP). Participants with an increased risk of type 2 diabetes completed a two-year lifestyle intervention and were subsequently followed for approximately nine years. The analysis focused on individuals who were able to achieve substantial and sustained long-term weight reduction.
“We were particularly interested in whether individuals in risk clusters 3 and 5 differed from those in other clusters with regard to improvements in blood glucose levels and the prevention of type 2 diabetes,” explains Professor Norbert Stefan, the lead author of the study. “We were very surprised to find that, despite a large and sustained weight loss of 8% and after a very long follow-up period of 9 years, individuals in risk cluster 5 showed increasing blood glucose levels, declining insulin secretion, and a persistently high risk of type 2 diabetes.”
Fatty Liver and Insulin Resistance May Explain the Findings
Why does lifestyle intervention protect individuals in risk cluster 5 less effectively against diabetes? The authors examined mechanisms that could explain the unfavorable metabolic trajectory observed in this group. Their data suggest that insulin resistance—most likely caused by pronounced fatty liver disease and fatty liver–related impairment of insulin secretion from pancreatic beta cells—led to rising blood glucose levels in individuals in cluster 5.
These findings are consistent with earlier observations showing that fatty liver disease and insulin resistance are the dominant pathophysiological mechanisms in individuals classified in Tübingen’s type 2 diabetes risk cluster 5, making them particularly susceptible to type 2 diabetes and cardiovascular disease.
Precision Prevention Strategies Are Needed
The present results indicate that individuals in risk cluster 5 do not benefit to the same extent from lifestyle interventions as those in other clusters, even with significant and sustained weight loss—particularly with respect to glucose metabolism. If these findings are confirmed in a prospective study, a more tailored approach to diabetes prevention will be required, in which high-risk phenotypes such as cluster 5 may need more intensive or targeted interventions.
Original publications:
Meier CZ, Wagner R, Ganslmeier M, Kantartzis K, Heni M, Peter A, Jumpertz-von Schwartzenberg R, Machann J, Schick F, Birkenfeld AL, Häring HU, Fritsche A, Stefan N. Different Metabolic Responses to Long-term Weight Loss After Lifestyle Intervention Among Type 2 Diabetes Risk Clusters: Results From the TULIP Study. Diabetes. 2026 Apr 13:db250757. doi: 10.2337/db25-0757. Online ahead of print.
* Wagner R, ..., Häring HU, Fritsche A. Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nat Med. 2021 Jan;27(1):49-57. doi: 10.1038/s41591-020-1116-9. Epub 2021 Jan 4. PMID: 33398163.
Scientific Contact:
Prof. Dr. Norbert Stefan
Helmholtz Munich
University Hospital Tübingen
German Center for Diabetes Research (DZD)
Phone: +49 7071 2980390
E-Mail: norbert.stefan@med.uni-tuebingen.de
The German Center for Diabetes Research (DZD e.V.) is one of the eight German Centers for Health Research. It brings together experts in the field of diabetes research and combines basic research, epidemiology and clinical application. The aim of the DZD is to make a significant contribution to the successful, customized prevention, diagnosis and treatment of diabetes mellitus through a novel, integrative research approach. www.dzd-ev.de/en
Helmholtz Munich is a biomedical research center of excellence. Its mission is to develop groundbreaking solutions for a healthier society in a rapidly changing world. Interdisciplinary research teams focus on environmental diseases, in particular the treatment and prevention of diabetes, obesity, allergies and chronic lung diseases. The Institute of Diabetes Research and Metabolic Diseases of Helmholtz Munich is affiliated with the University of Tübingen. www.helmholtz-munich.de/en.
Founded in 1805, Tübingen University Hospital is one of the leading centers of university medicine in Germany. Being one of the 33 university hospitals in Germany, it contributes to the successful combination of high-performance medicine, research and teaching. More than 400,000 inpatients and outpatients from all over the world benefit from this combination of science and practice every year. The clinics, institutes and centers bring together specialists from a wide range of disciplines under one roof.
The experts work together on an interdisciplinary basis and offer each patient the best possible treatment based on the latest research findings. The University Hospital of Tübingen is researching for better diagnoses, therapies and chances of recovery. Many new treatment methods are being clinically tested and applied here. In addition to diabetology, research in Tübingen focuses on neurosciences, oncology, immunology, infection research and vascular medicine. Over the past 25 years, the Chair of Diabetology / Endocrinology has been a center of interdisciplinary research, particularly involving surgery, radiology and laboratory medicine.
The discovery of prediabetes subtypes was only possible thanks to interdisciplinary collaboration. The University Hospital is a reliable partner of four of the six German Centers for Health Research initiated by the federal government. www.medizin.uni-tuebingen.de/en-de
