Normal Glucose Regulation May More Effectively Prevent T2D Than Weight Loss

Achieving prediabetes remission by reaching normal glucose regulation – based on American Diabetes Association criteria – may be more efficient in preventing type 2 diabetes (T2D) than reaching weight loss goals.1

In a post hoc analysis of the Prediabetes Lifestyle Intervention Study (PLIS), investigators demonstrated the achievability of prediabetes remission without weight loss or gain. Underlying mechanisms also improved insulin sensitivity, beta-cell function, and increments in beta-cell-GLP-1 sensitivity. However, these benefits were limited by the necessity for the distribution of weight to subcutaneous deposits rather than visceral deposits.1

“Our data provide new support for the importance of implementing glycemic targets into current treatment guidelines to improve T2D prevention, and show that the sole assessment of weight trajectories without body fat distribution is not adequately informative for the pursuit of treatment success,” wrote Arvid Sandforth, MD, German Center for Diabetes Research, and colleagues.1

PLIS was a stratified randomized multicenter trial involving 8 university hospitals in Germany. Investigators diagnosed prediabetes from fasting and 2-h postchallenge glucose (2hPG) levels after a standardized oral glucose tolerance test (OGTT). Patients were also screened via measurement of liver fat content, insulin sensitivity, and insulin secretion.2

These results were used to stratify patients as high- or low-risk. High risk was characterized by a reduced insulin secretion and/or insulin resistance and an elevated liver fat content. Low-risk participants were randomly assigned to receive either no lifestyle intervention (LI) or a conventional LI, while high-risk patients were randomized to receive either conventional LI or an intensive LI.2

The primary outcome measure of 2hPG was measured with an OGTT after 12 months, and an intermediate OGTT was performed after 6 months. Secondary outcome measures included liver fat content, insulin sensitivity and secretion, and cardiovascular risk. Investigators also included a tertiary outcome of LI adherence.2

PLIS included a total of 1105 patients, all of whom were given the intervention for 12 months and followed up for ≤9 years with metabolic phenotyping, such as whole-body magnetic resonance imaging for body fat distribution assessment. A total of 234 (21.2%) patients either did not lose weight or gained weight during the 12-month interventional period – of these, 51 returned to normal glucose regulation (NGR) and were designated “responders,” while 183 were “nonresponders.”1

At long-term follow-up, investigators in PLIS found participants reaching weight-loss-induced prediabetes remission had a 73% reduced risk of T2D development compared to those who only met the weight loss goal without remission. Based on this data, the post-hoc analysis found that remission of prediabetes without weight loss is a reproducible response to an LI in a significant proportion of participants. Non-weight-loss-associated prediabetes remission was also characterized by higher insulin sensitivity and improved insulin secretion, contrasting the response from weight-loss-induced prediabetes.1

The analysis showed that prediabetes remission without weight loss was protective from T2D development with a risk ratio (RR) reduction >70%, as well as associated it with a combination of higher insulin sensitivity and improved insulin secretion. Investigators noted these factors as highlighting distinct physiological mechanisms that underlie non-weight-loss-induced remission of prediabetes.1

“In light of the current data, we recommend achieving metabolic health by incorporating glycemic targets to reach NGR (prediabetes remission) in addition to weight loss, thereby optimizing T2D risk reduction through a precise prevention approach,” Sandforth and colleagues wrote. “Specifically, LI needs to be tailored to the goal of prediabetes remission.”1

References

1. 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

2. Fritsche A, Wagner R, Heni M, et al. Different Effects of Lifestyle Intervention in High- and Low-Risk Prediabetes: Results of the Randomized Controlled Prediabetes Lifestyle Intervention Study (PLIS). Diabetes 1 December 2021; 70 (12): 2785–2795. https://doi.org/10.2337/db21-0526