β‐cell recovery revisited: Is prediabetes remission driven by insulin sensitivity or β‐cell function?

The concept of “prediabetes remission”—the reversion from dysglycemia to normoglycemia—has gained substantial attention in recent years. While remission of type 2 diabetes is now widely accepted as biologically plausible and clinically meaningful1, 2, the mechanistic basis of remission at the prediabetes stage remains incompletely defined. In this context, Retnakaran and colleagues provide important evidence demonstrating that recovery of β-cell function, rather than improvement in insulin sensitivity alone, is the principal determinant of prediabetes remission3. Previous investigations have reported conflicting results regarding the prediabetes remission. Analyses from the Prediabetes Lifestyle Intervention Study suggested that enhanced insulin sensitivity may drive remission without substantial improvement in β-cell function4. In contrast, findings from the Diabetes Prevention Program Outcomes Study indicated that preservation of β-cell function was more closely associated with regression to normoglycemia5. The present study was specifically designed to address this inconsistency. In a well-characterized prospective postpartum cohort, women with incident prediabetes underwent longitudinal metabolic assessment using serial oral glucose tolerance tests. Insulin sensitivity was evaluated using the Matsuda index and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), whereas β-cell compensation was assessed using Insulin Secretion–Sensitivity Index-2 (ISSI-2) and insulinogenic index (IGI)/fasting plasma insulin (FPI)—indices selected because of their mathematically validated hyperbolic relationship between insulin secretion and sensitivity. Although both insulin sensitivity and insulin secretion improved in individuals who achieved remission, changes in log ISSI-2 emerged as the strongest predictor of remission, exceeding the contribution of changes in insulin sensitivity. These results challenge the view that remission of prediabetes is mechanistically distinct from remission of diabetes. Instead, the study supports that β-cell compensation plays a central role across the entire dysglycemic continuum (Figure 1). This study raises several important implications to the field. First, prediabetes should not be viewed as a condition of isolated insulin resistance. A significant impairment in β-cell compensation is already evident at this stage. This is biologically plausible, as even modest elevations in fasting glucose (100–114 mg/dL), within the prediabetic range, are associated with a substantial reduction in first-phase insulin response to approximately 40% of normal, with complete loss occurring as glycemia rises further6. This suggests that β-cell dysfunction begins earlier than often appreciated. Second, strategies aimed at preserving or restoring β-cell function may need to be initiated at the prediabetes stage. Interventions targeting β-cell stress, glucotoxicity, or dedifferentiation could be as relevant in prediabetes as in early type 2 diabetes7, 8. Nevertheless, an important limitation persists, as no standardized and clinically practical approach exists for precisely quantifying functional β-cell mass9. Recent work by Ha and colleagues suggests that β-cell function may be estimated without direct insulin measurement10, raising the possibility that emerging approaches—particularly when combined with widespread continuous glucose monitoring—could offer novel, practical tools to approximate functional β-cell capacity11. Accurate and clinically feasible assessment of functional β-cell mass would facilitate earlier intervention aimed at restoring β-cell function. Another important unanswered question concerns the biological signals underlying differences between remission and non-remission groups. Baseline β-cell reserve may play a critical role, reflecting an individual's metabolic compensatory capacity. Indeed, in the study by Retnakaran et al.,3 baseline ISSI-2 values were significantly higher in participants who later achieved remission, suggesting that pre-existing β-cell resilience may influence reversibility. Beyond this, additional biological mediators—including extracellular vesicles, metabolomic profiles, and proteomic signatures—may modulate β-cell adaptation but remain insufficiently characterized12, 13. Future investigations incorporating integrated multi-omics strategies will be essential to clarify these mechanistic pathways. Despite the clarity of the message, several considerations warrant attention. The cohort consisted of postpartum women, and although the authors argue that the mechanisms are unlikely to differ fundamentally across sex or life stages, validation in broader and more diverse populations is necessary. The history of pregnancies could have influenced β-cell compensatory capacity, potentially rendering some individuals more susceptible to β-cell failure14. Moreover, in early prediabetes—particularly among certain populations such as Caucasians—β-cells may transiently compensate for insulin resistance with increased insulin secretion before decompensation occurs15. This heterogeneity suggests that prediabetes encompasses a spectrum of functional β-cell states, which may partly explain conflicting findings across studies3-5. This study shows that remission of diabetes and remission of prediabetes are not separate processes, but part of the same pathophysiological continuum. By demonstrating that improvement in β-cell compensation both accompanies and predicts restoration of normoglycemia, the authors reinforce the idea that reversible β-cell dysfunction is central throughout the dysglycemic trajectory. As remission is increasingly pursued as a treatment target, defining its biological mechanisms becomes essential. This study brings important clarity: even at the stage of prediabetes, β-cell health remains pivotal. Recent advances in incretin-based therapies have demonstrated the capacity to reverse dysglycemia, including regression from prediabetes to normoglycemia16. However, long-term glycemic outcomes after discontinuation of incretin therapy remain uncertain. Weight regain following cessation of incretin therapy has been consistently reported, accompanied by modest increases in HbA1c and fasting glucose compared with levels during incretin treatment17, 18. However, glycemic trajectories relative to the pre-treatment baseline—particularly when assessed using detailed metabolic evaluations such as oral glucose tolerance tests—remain insufficiently characterized. The impact of prolonged incretin exposure on β-cell function also remains incompletely understood. Whether incretin-based therapy initiated during the prediabetes stage can produce durable improvements in β-cell function and reduce the long-term risk of dysglycemia warrants further investigation. This message may be particularly relevant in East Asian populations, which have traditionally been characterized by relatively lower β-cell mass, although these phenotypic patterns appear to be evolving.9, 19, 20 Prospective studies specifically evaluating prediabetes remission in East Asian cohorts remain limited and represent an important direction for future investigation. The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2025. The authors declare no conflict of interest. Approval of the research protocol: N/A. Informed consent: N/A. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.