A major new study reveals that up to one in five people with prediabetes can return to normal blood sugar without losing weight, altering how doctors think about preventing type 2 diabetes.
Study: Prevention of type 2 diabetes through prediabetes remission without weight loss. Image credit: Anna Rogalska/Shutterstock.com
In a recent Nature Medicine article, researchers investigated whether prediabetic individuals can return to normal glucose regulation without losing weight, a finding that could be key to preventing type 2 diabetes (T2D). They found that prediabetes remission occurred despite no weight loss (often with slight weight gain), and was associated with healthier fat distribution, improved β-cell function, and enhanced insulin sensitivity.
Background
T2D affects over 460 million people worldwide and is a leading cause of death due to its complications, including neuropathy, cardiovascular disease, and chronic kidney disease. The global burden of T2D is expected to increase substantially by 2050. Poor diet quality is the main driver, with the greatest impact in low- and middle-income countries with limited treatment access. Prevention strategies are essential to reducing the worldwide burden of T2D.
Prediabetes is a metabolic condition in which blood sugar levels are higher than normal but not high enough to meet the diagnostic criteria for type 2 diabetes (T2D). It is typically defined by impaired glucose regulation, such as elevated fasting glucose, impaired glucose tolerance on an oral glucose tolerance test, or increased glycated hemoglobin (HbA1c), that falls below the threshold used to diagnose diabetes.
It is the most significant risk factor for T2D. The annual progression rate is 5-10%, with a lifetime risk of up to ~74%. It also independently increases the risk of vascular, cancer, and neurodegenerative diseases.
Previous research has shown that restoring normal glucose regulation, even temporarily, lowers the risk of developing T2D and related complications. The Prediabetes Lifestyle Intervention Study (PLIS) introduced the concept of prediabetes remission. Remission is achieved when normal glucose levels are restored, often through weight loss. Such remission substantially lowers T2D risk and related organ damage. This emphasizes the importance of glucose regulation in preventive strategies.
About the Study
Researchers conducted a post hoc analysis of PLIS, a randomized, controlled, multicenter trial conducted in Germany between 2012 and 2016. Adults aged 18 to 75 years with prediabetes, defined by impaired fasting glucose and/or impaired glucose tolerance, were recruited. Participants were stratified by diabetes risk based on insulin resistance, insulin secretion, and liver fat and then randomized to conventional or intensified lifestyle intervention or control.
This analysis included only participants who did not lose weight over 12 months. If glucose regulation returned to normal, they were classified as responders, and if it did not, they were classified as non-responders.
Glucose metabolism was assessed by oral glucose tolerance tests (OGTT) with repeated blood sampling. Insulin, C-peptide, liver fat, visceral and subcutaneous fat, and muscle fat were measured using standardized assays, MRI, or spectroscopy. Additional analyses included inflammatory markers, adipokines, incretins, and a visceral adipose tissue (VAT) polygenic risk score, with no significant group differences observed. Lifestyle adherence was monitored through food diaries, fitness testing, and physical activity assessments.
Findings were validated in a second cohort from the U.S. Diabetes Prevention Program (DPP), focusing on participants who also did not lose weight during the first 12 months. Statistical analyses applied mixed-effects models and corrected for multiple testing.
Key Findings
The study followed 1,105 individuals with prediabetes from the PLIS. Among the 234 participants who did not lose weight (or even gained some) during the 12-month program, 51 achieved remission while 183 did not. Notably, remission occurred independently of changes in body weight, body composition, physical activity, or aerobic fitness.
Responders showed distinct metabolic improvements. Their insulin sensitivity rose significantly, while non-responders showed no change. In addition, responders exhibited enhanced insulin secretion and better β-cell function, changes not typically observed in weight-loss–driven remission.
Body fat distribution also differed: responders stored more fat in subcutaneous adipose tissue (SCAT) while avoiding increases in VAT, leading to a higher SCAT/VAT ratio. This healthier fat pattern was linked with higher adiponectin levels, consistent with improved insulin sensitivity.
Other potential mechanisms, such as inflammation, liver fat accumulation, or genetic predisposition, did not explain remission. Notably, responders had improved glucagon regulation and greater sensitivity of β-cells to glucagon-like peptide-1 (GLP-1), supporting better glucose control. Over long-term follow-up, remission without weight loss lowered T2D risk by ~71%, similar to weight-loss remission. The DPP confirmed these findings, strengthening their validity.
Conclusions
This study demonstrates that up to 22% of participants can remit prediabetes without weight loss and provides strong protection against T2D, comparable to weight-loss-induced remission. The key factor appears to be fat distribution: responders accumulated more subcutaneous than visceral fat, which was linked to greater insulin sensitivity, β-cell function, and improved GLP-1 sensitivity.
Exercise and dietary composition may have contributed to these favorable outcomes. The findings highlight the need to expand clinical guidelines beyond weight loss alone, emphasizing remission to normal glucose regulation as a primary prevention target.
Strengths include replication of results in the DPP cohort and detailed metabolic profiling. Limitations are the post hoc design, reliance on surrogate OGTT measures, and potential residual confounding.
Overall, the study underscores that metabolic health and glycemic remission, not weight loss alone, should guide precision prevention strategies for T2D.
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