Researchers report that people assigned to Tübingen’s type 2 diabetes risk cluster 5 continued to experience rising blood sugar, a sharp decline in insulin production, and a consistently elevated risk of developing diabetes. These unfavorable changes occurred even among people who lost a substantial amount of weight and maintained that loss for years.

The findings come from scientists at the German Center for Diabetes Research (DZD), the University Hospital Tübingen and Helmholtz Munich. The results were published in the scientific journal Diabetes.

Six Distinct Type 2 Diabetes Risk Groups

Several years ago, DZD researchers separated people at risk of type 2 diabetes into six clearly defined clusters. These groups differ considerably in how often diabetes develops and how diabetes related complications progress.

Clusters 3 and 5 were identified as having an especially high likelihood of developing type 2 diabetes. In the latest analysis, researchers examined whether long-term weight loss and lifestyle-based diabetes prevention produced different results across these risk groups.

Cluster 5 Remains Vulnerable Despite Weight Loss

The researchers analyzed information from the Tübingen Lifestyle Intervention Program (TULIP). People with an increased risk of type 2 diabetes participated in a two-year lifestyle program and were then monitored for approximately nine years.

The analysis concentrated on participants who achieved substantial weight loss and successfully maintained it over the long term.

“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 Drive the Risk

The researchers also investigated why lifestyle intervention appeared to provide less protection for people in cluster 5. Their analysis focused on the biological mechanisms that might explain the group’s worsening metabolic health.

The results suggest that insulin resistance played a major role. This resistance was most likely linked to severe fatty liver disease. Fat accumulation in the liver may also have impaired the ability of pancreatic beta cells to release insulin, contributing to higher blood sugar levels in people in cluster 5.

The findings support earlier evidence showing that fatty liver disease and insulin resistance are the main disease processes affecting people in Tübingen’s type 2 diabetes risk cluster 5. These characteristics may leave them especially vulnerable to both type 2 diabetes and cardiovascular disease.

Personalized Diabetes Prevention May Be Necessary

The results indicate that people in cluster 5 may not receive the same metabolic benefits from lifestyle intervention as people in other risk groups. This was true even when they achieved substantial and lasting weight loss, particularly when researchers examined blood sugar regulation.

If future prospective research confirms the findings, diabetes prevention may need to become more personalized. People with high-risk biological profiles such as cluster 5 may require more intensive care or treatments designed to address their specific metabolic problems.