Highlight
- Lower baseline neutrophil counts are strongly associated with increased likelihood of type 2 diabetes remission (T2DM) after a 5-year Mediterranean diet intervention, but not with a low-fat diet.
- Neutrophil-related ratios normalized to other blood components (NER, NHR) also predict remission and enhance model accuracy.
- Responders who achieved remission show significant decreases in neutrophil counts over time with improvements in insulin sensitivity and beta-cell function.
- Immune cell profiling may aid patient stratification and prognostication in dietary management of T2DM, especially in those with coronary heart disease.
Study Background and Disease Burden
Type 2 diabetes mellitus (T2DM) presents a growing global health challenge due to its high prevalence, associated cardiovascular complications, and substantial economic burden. Coronary heart disease (CHD) frequently coexists with T2DM, compounding morbidity and mortality risks. Although lifestyle interventions centered on diet and physical activity can induce remission of early T2DM, variability in treatment responses highlights unknown pathophysiological factors influencing disease resolution. Emerging evidence points to immune dysregulation, particularly involving innate immune cells like neutrophils, as a contributory mechanism linking inflammation and insulin resistance. The CORDIOPREV study investigates how long-term dietary patterns influence neutrophil profiles and their associations with T2DM remission, aiming to identify immune-related biomarkers predictive of metabolic improvement in patients with CHD.
Study Design
This study analyzed data from 183 newly diagnosed T2DM patients enrolled in the CORDIOPREV randomized controlled trial (ClinicalTrials.gov ID: NCT00924937), focusing on those not receiving glucose-lowering pharmacotherapy at baseline. Patients were randomized to either a Mediterranean diet or a low-fat diet and followed for 5 years. Responders (n=73) were defined as those achieving T2DM remission—a state of normoglycemia without pharmacological treatment—while Non-Responders (n=110) did not reach remission during follow-up. Blood measurements included absolute neutrophil counts and specific neutrophil-related ratios normalized by erythrocyte, basophil, lymphocyte counts and HDL cholesterol (NER, NBR, NLR, NHR), taken at baseline and at 5 years.
Key Findings
Patients in the lowest tertile of baseline neutrophil count following the Mediterranean diet had a significantly higher likelihood of achieving T2DM remission compared to those in the highest tertile (adjusted hazard ratio [HR] 4.23; 95% confidence interval [CI]: 1.53-11.69). This association was not observed in the low-fat diet cohort, underscoring a diet-specific effect on immune-metabolic interactions. Corroboratively, neutrophil-related ratios NER and NHR showed similar predictive trends.
A predictive model incorporating clinical variables and neutrophil parameters achieved an area under the receiver operating characteristic curve (AUC) of 0.783 (95% CI: 0.680–0.822), highlighting substantial accuracy in distinguishing patients likely to remit.
At 5 years, Responders exhibited significantly lower neutrophil counts than Non-Responders (p=0.006) and demonstrated a notable decline in neutrophil levels from baseline (p=0.001). Notably, in Responders on the Mediterranean diet, this neutrophil reduction correlated with significant improvements in insulin sensitivity (p=0.011) and beta-cell function, measured as Disposition Index (p=0.018). These findings support a mechanistic link between lowered systemic inflammation, immune cell modulation, and restoration of glucose homeostasis.
Expert Commentary
The interplay between immunity and metabolic disease is a rapidly evolving field. Neutrophils, traditionally viewed as first-line defenders against infection, are increasingly recognized for their role in sterile inflammation and tissue dysfunction seen in metabolic disorders. This study robustly demonstrates that lower neutrophil burden associates with favorable metabolic outcomes under a Mediterranean dietary pattern, thus suggesting immune profiling as a valuable adjunct in personalizing diabetes management.
While compelling, these results require cautious interpretation. The observational nature of neutrophil associations does not prove causality, and factors influencing neutrophil counts (e.g., infections, stress) should be considered. Additionally, the study’s focus on patients with CHD may limit generalizability to broader T2DM populations. Replication in diverse cohorts and mechanistic studies elucidating neutrophil functional changes in diet-mediated remission will enhance translational relevance.
Conclusion
This analysis from the CORDIOPREV study supports neutrophil count as a promising biomarker for predicting T2DM remission in patients adhering to a Mediterranean diet, potentially through modulation of insulin sensitivity and pancreatic beta-cell function. Integrating immune parameters into clinical assessment could optimize dietary intervention strategies, improving long-term metabolic outcomes in patients with coexisting coronary disease and diabetes. Future research should explore targeted immunometabolic pathways as novel therapeutic avenues in T2DM remission.
References
1. Boughanem H, Gutierrez-Mariscal FM, Arenas-de Larriva AP, et al. Effect of long-term Mediterranean versus low-fat diet on neutrophil count, and type 2 diabetes mellitus remission in patients with coronary heart disease: results from the CORDIOPREV study. Nutr Diabetes. 2025;15(1):11. doi:10.1038/s41387-025-00360-3.
2. Taylor R. Type 2 diabetes remission: The next chapter. Diabetes Care. 2019;42(6):1093-1096.
3. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98-107.
4. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141-50.
