Weight loss alone may not be enough to prevent progression from prediabetes to type 2 diabetes (T2D) in some patients, according to new research.
A nearly 9-year follow-up of participants in the Tübingen Lifestyle Intervention Program (TULIP) found that those classified as having a high-risk “cluster 5” phenotype — characterized by severe insulin resistance, elevated BMI, and older age — continued to experience worsening glycemic control and declining β-cell function despite clinically meaningful and sustained weight loss.
The findings add to a growing body of evidence that diabetes prevention strategies may need to extend beyond weight loss alone and instead be tailored to specific metabolic phenotypes.
“It is important to know the risk of developing T2D before a lifestyle intervention,” lead author Norbert Stefan, MD, PhD, professor of clinical and experimental diabetology at the University of Tübingen and Institute of Diabetes Research and Metabolic Diseases, Helmholtz Centre, Munich, Germany, told Medscape Medical News.
“Alternative or intensified interventions should be considered for people in Tübingen T2D risk cluster 5,” he said.The study was published online in Diabetes.
Search for Long-Term Weight-Loss Benefits
“In 2021, we identified six clusters of people at different risks of T2D and/or diabetes-related comorbidities,” Stefan said.
Participants were assigned to Tübingen T2D risk clusters using criteria derived from the TULIP and Tübingen Diabetes Family Study cohorts and later replicated in the London-based Whitehall II study. Cluster classification incorporated sex, BMI, waist and hip circumference, fasting glucose, 2-hour oral glucose tolerance test values, triglycerides, and HDL cholesterol. Stefan noted that the TULIP classification is more complex than the Whitehall II model because it additionally includes liver fat content and visceral fat mass.
Lifestyle interventions aimed at weight loss generally improve glucose levels, insulin secretion, and insulin sensitivity, thereby helping prevent T2D, Stefan explained. However, “there is quite some heterogeneity in these responses. … People in cluster 3 (mostly low insulin production) and cluster 5 (older age, higher BMI, and severe insulin resistance) had a high risk of progression to diabetes.”
TULIP investigators therefore examined whether people in clusters 3 and 5 differed from those in other clusters in long-term changes in insulin sensitivity, insulin secretion, and progression to T2D, particularly among those who maintained weight loss over time.
A total of 190 participants completed the 24-month lifestyle intervention and were followed for 8.7 years.
At baseline, cluster 5 participants had a mean age of 53 years, making them older than participants in clusters 1, 2, 4, and 6 (mean age, 47) and slightly younger those in cluster 3 (mean age, 54).
Overall, 60 participants achieved weight loss of at least 3%, with a mean reduction of 8% at long-term follow-up.
Among those who sustained this degree of weight loss, cluster 5 participants (n = 17) experienced significantly greater increases in adjusted fasting glycemia compared with participants in clusters 1, 2, 4, and 6 and those in cluster 3 (n = 33 and n = 10, respectively; all P < .05).
Participants in cluster 5 also demonstrated larger declines in adjusted insulin secretion compared with participants in cluster 3 and clusters 1, 2, 4, and 6 (P = .01 and P = .05, respectively).
Notably, 41% of cluster 5 participants eventually developed T2D, compared with none of those in clusters 1, 2, 4, and 6 and only 10% of participants in cluster 3.
Stefan said he and his colleagues were “very surprised” that, despite sustained weight loss averaging 8% over nearly 9 years, cluster 5 participants continued to show worsening glucose levels, declining insulin secretion, and persistently elevated T2D risk.
The authors proposed that cluster 5 individuals may experience a harmful combination of severe insulin resistance and “initially compensatory hypersecretion of insulin,” ultimately leading to progressive decline in β-cell function.
Fatty Liver’s Possible Role
The investigators hypothesized that fatty liver disease may be an important biological driver of these findings.
At baseline, cluster 5 participants had markedly higher liver fat content, 2.4-fold higher than participants in clusters 1, 2, 4, and 6, and 1.7-fold higher than those in cluster 3 (P = .002 and P = .018, respectively).
The researchers hypothesized that fatty liver may increase secretion of the hepatokine fetuin-A, which can promote inflammation, worsen insulin resistance, and impair glucose-induced insulin secretion. Among participants who maintained at least 3% long-term weight loss, baseline fetuin-A levels were highest in cluster 5 after adjustment for age, sex, and adiponectin.
For individuals in T2D cluster 5, “it may be more important to focus on interventions that specifically reduce liver fat content rather than body weight,” they suggested.
Stefan recommended additional targeted interventions for these patients, including adoption of a “healthy, mostly Mediterranean, diet.” He also suggested considering off-label metformin use for diabetes prevention in patients with prediabetes.
Precision Medicine Approach
Commenting on the findings for Medscape Medical News, Barbara Eichorst, MS, RD, vice president of healthcare programs at the American Diabetes Association, said the study is “highly relevant because it reinforces that people at risk for T2D are not metabolically homogeneous.”
She said the findings are particularly important because they “challenge the assumption that weight loss alone will universally prevent progression to T2D.” Instead, the study “highlights the complexity of insulin resistance, β-cell dysfunction, and liver fat biology, and supports a more individualized and pathophysiology-driven approach to diabetes prevention and obesity care.”
The findings contribute to a growing body of evidence supporting precision medicine in diabetes prevention, Eichorst added. She encouraged clinicians to look beyond body weight and assess broader metabolic phenotypes, such as insulin sensitivity, insulin secretion, liver fat, and overall cardiometabolic risk.
Scott Isaacs, MD, past president of the American Association of Clinical Endocrinology and adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia, also commented on the findings for Medscape Medical News.
“The take-home message is that while lifestyle change and weight loss remain the foundation of diabetes management, older, markedly insulin-resistant patients with metabolic dysfunction-associated steatotic liver disease will often need earlier, more intensive, and liver-targeted pharmacologic or surgical interventions rather than lifestyle alone,” Issacs said.
TULIP was supported by a grant from the Deutsche Forschungsgemeinschaft. The current study was supported by a grant from the German Federal Ministry of Education and Research to the German Centre for Diabetes Research. Stefan and coauthors, Eichorst, and Isaacs reported no relevant financial relationships.
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