Revisiting diabetes prevention

October 29, 2025 — 08:30 🕑 5 minutes

Revisiting diabetes prevention

Current guidelines focusing on weight loss for diabetes prevention overlook the importance of achieving normal glucose regulation, regardless of weight loss.

Prediabetes is the most significant risk factor for type 2 diabetes (T2D), with an annual progression rate of 5–10 % and a lifetime progression risk of 74 %. Current prevention strategies primarily focus on reducing body weight by 5–10 % to lower diabetes risk.

However, a new post hoc analysis of the Prediabetes Lifestyle Intervention Study (PLIS) reports that about one in five individuals with prediabetes can achieve normal glucose regulation (NGR) without losing weight or in some cases even while gaining weight. These results, recently published in Nature Medicine, challenge the role of weight loss as the primary target in prediabetes care.

“It is important to revisit the role of weight loss in diabetes prevention, because remission of prediabetes – returning to NGR – can occur without weight loss and still deliver a reduction in incident T2D of over 70 % in long-term follow-up,” explains corresponding author Andreas Birkenfeld, Head of the Diabetology, Endocrinology and Nephrology at the University Hospital Tübingen and Director of the Institute for Diabetes Research and Metabolic Diseases (IDM) at Helmholtz Munich. These results could inform future guidelines such as the EASD guideline for T2D prevention, which Birkenfeld and others are currently developing.

One in five achieves normal glucose regulation without weight loss

The PLIS trial enrolled 1,105 individuals with prediabetes, who completed a 12-month lifestyle intervention. They were followed for up to nine years, during which they underwent oral glucose tolerance tests (OGTTs) and MRI-based body fat distribution analysis. Of all participants, 234 (21.2 %) did not lose or even gained weight during the intervention. Among this group included in the post hoc analysis, 51 (21.8 %) reached NGR and were classified as responders, 183 (78.2 %) were nonresponders.

“The responders improved insulin sensitivity and insulin secretion, showed enhanced β-cell-GLP-1 sensitivity with better glucagon suppression, and had a 71 % lower risk of T2D compared to nonresponders,” says last author Reiner Jumpertz-von Schwartzenberg, Professor at the University Hospital Tübingen and Head of the Clinical Study Centre at the IDM Helmholtz Munich. The findings were replicated in a U.S. Diabetes Prevention Program (DPP) cohort.

Overall, these results support the idea that the glycaemic control has a weight-independent component in diabetes prevention. Furthermore, the authors report that prediabetes remission without weight loss is comparably protective for T2D development as prediabetes remission with weight loss, with a relative risk reduction of 71 % over up to 10 years (RR = 0.29, 95 % CI = 0.09–0.91, p = 0.02; Figure 1).

Left: The proportion of individuals without T2D in the responder and nonresponder groups over time. Glycaemic categories (T2D, prediabetes, and normal glucose regulation) over the follow-up period.

Improvements in glucose metabolism

The study investigated several potential mechanisms for non-weight-loss prediabetes remission. Responders demonstrated higher insulin sensitivity and insulin secretion, improved β-cell function, and greater β-cell-GLP-1 responsiveness. This suggests that the underlying mechanisms differ between individuals who lose weight and those who do not. Notably, in a study published by the group two years ago, they provided evidence that weight loss-induced prediabetes remission is mainly mediated by an increase in insulin sensitivity when groups were matched for weight loss.

Responders also showed enhanced glucagon suppression and a favourable GLP-1 response pattern. Other factors, such as inflammatory markers, hormonal factors, and very-low-density lipoprotein (VLDL) palmitate were examined but did not appear to play a major role. However, the authors did find evidence of increased adiponectin secretion in responders, which may be related to fat redistribution and could further improve insulin sensitivity.

Fat distribution emerges as a key factor

Given the link between insulin sensitivity and secretion and ectopic adipose tissue deposition, the authors assessed the accumulation in both subcutaneous (SCAT) and visceral adipose tissue (VAT). MRI analyses revealed that, while both groups remained at or gained weight, responders predominantly stored excess energy in SCAT, whereas nonresponders accumulated VAT.

Consequently, responders showed a substantially higher SCAT/VAT ratio after the intervention, indicating healthier fat distribution. “This VAT-sparing pattern aligns with the observed gains in insulin sensitivity, higher adiponectin, and improved β-cell-GLP-1 responsiveness – reframing remission as a function of fat distribution and tissue function, not just body mass change,” says Jumpertz-von Schwartzenberg. Birkenfeld adds: “The data show that not the amount of body fat counts, but the location. We need more research to better understand how to specifically achieve such a re-distribution of fat, but as far as we know, physical exercise and intake of unsaturated fatty acids is helpful.”

Implications for future EASD guidelines

Birkenfeld is one of the key figures involved in developing the upcoming EASD guideline on T2D prevention. “Guideline development at the EASD is a rigorous, evidence-based process: recommendations follow the strength, consistency, and quality of the data – nothing else,” he explains. “Within that framework, our findings indicate that the restoration of normoglycaemia is a clinically meaningful, patient-relevant goal in prediabetes, associated with a lower progression to T2D, and a more favourable metabolic risk profile and less complications. Notably, this goal has just been adopted in the new treatment algorithm for people with obesity and prediabetes by The European Association for the Study of Obesity – another strictly evidence-based guideline – thus underscoring that this endpoint is now entering contemporary practice standards.”

Emphasizing the results of the PLIS post hoc study, Birkenfeld underlines that current prevention guidelines focus mainly on weight loss targets risks, overlooking another important patient-relevant goal. It will be important to consider prediabetes remission in addition to weight goals, since prediabetes remission has been shown to have a long-standing legacy effect on diabetes prevention," he concludes.

Key Points:
• In a post hoc analysis of the PLIS trial, diabetes remission without weight loss occurred in about 22 % of individuals with a relative risk reduction for developing T2D of 71 %.
• MRI-based analyses of fat distribution show that not body weight determines metabolic improvement, but that responders store fat subcutaneously rather than viscerally, improving insulin sensitivity and β-cell function.
• The authors argue that normal glucose regulation (NGR) should be considered as a primary therapeutic goal in diabetes prevention guidelines, rather than focusing on weight-loss targets alone.

To read this paper visit: Sandforth A, Arreola EV, Hanson RL, et al. Prevention of type 2 diabetes through prediabetes remission without weight loss. Nat Med. 2025;31(10):3330-3340. doi:10.1038/s41591-025-03944-9.