Association between dental pulp necroptosis-related signaling and elodont incisor growth retardation in hyperglycemic rats.

INTRODUCTION

Although type 1 diabetes (T1D) induces systemic allostatic load, whether sustained hyperglycemia is accompanied by necroptosis-related signaling within the dental pulp (DP) niche and its impact on the developmental kinetics of continuously growing elodont incisors remains unclear.

OBJECTIVES

This study investigated whether sustained hyperglycemia was accompanied by enhanced RIPK3-MLKL necroptosis-related signaling within the DP niche and whether these molecular alterations coincided with attenuation of elodont incisor growth.

METHODS

T1D was induced in Sprague-Dawley rats using streptozotocin (65 mg/kg). Systemic metabolic profiles, necroptotic markers in serum/dental tissues (immunohistochemistry, ELISA, and Western blotting), and mandibular incisor growth (a standardized notch-creation method for 49 days) were evaluated. Group differences were assessed primarily using two-sided Welch's t-tests, with exact Mann-Whitney U tests for sensitivity analyses, while discriminative performance was evaluated using receiver operating characteristic (ROC-AUC) and precision-recall (PR curve-based AP) analyses.

RESULTS

Hyperglycemic rats exhibited impaired weight gain, systemic inflammatory induction (elevated NLR/MLR), and elevated hepatic stress markers. Molecular profiling demonstrated increased oxidative damage (4-HNE) and necroptosis-related molecular alterations in dental tissues and DP-derived cells. Incisor growth rates differed significantly at the Phase-Transition (0.532 vs. 0.400 mm/day; Welch's p = 0.024), reaching definitive retardation in Phase-2 (0.594 vs. 0.408 mm/day; p < 0.001). Discriminatory performance improved from the Phase-Transition (ROC-AUC = 0.693; AP = 0.784) to Phase-2 (ROC-AUC = 1.000; AP = 1.000). Glycemic reversion was accompanied by normalization of necroptosis-related markers and incisor growth kinetics.

CONCLUSION

Hyperglycemia-induced incisor growth retardation is associated with increased oxidative stress, altered PGAM5 expression, and enhanced RIPK3-MLKL necroptosis-related signaling in dental tissues and DP-derived cells. Translationally, longitudinal evaluation of elodont incisor growth kinetics could serve as a minimally invasive phenotypic indicator of metabolic dysregulation in preclinical diabetic models and support refinement under the 3Rs principle.