Front Endocrinol (Lausanne). 2026 Jun 2;17:1777636. doi: 10.3389/fendo.2026.1777636. eCollection 2026.
ABSTRACT
BACKGROUND: Type 2 Diabetes Mellitus (T2D) is a metabolic disorder with increasing prevalence worldwide. Fractures are increased in people with T2D. Black patients have higher bone mineral density than White patients, suggesting the potential for distinct mechanisms for fracture within specific populations.
METHODS: To test whether changes to metabolism during T2D may contribute to skeletal fragility, we analyzed 465 targeted metabolites in serum collected at baseline from 571 participants (average age 62.1 years) in the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD, ClinicalTrials.gov NCT00000620), a randomized clinical trial of patients with T2D. Participants with T2D were enrolled and serum was collected at baseline. These serum samples were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. We focused exclusively on ACCORD participants who were Black, an understudied population with regards to fracture risk. Following enrollment, participants were randomized to intensive or standard glycemia strategies, which did not affect fracture or fall risk. Using the longitudinal data from ACCORD BONE, we compared the baseline serum metabolome of participants who later fractured with those who did not fracture.
RESULTS: Individual metabolite analysis revealed circulating metabolites that were significantly different at baseline in those that fractured versus those who did not. One metabolite had both adjusted and unadjusted p-values that reached significance: 7,8-dihydrofolate, which is involved in folate-dependent one-carbon metabolism, was greater in participants who later fractured compared to those who did not fracture. Importantly, several metabolites related to the tricarboxylic acid cycle were reduced in participants who later fractured, with significant unadjusted p-values.
CONCLUSION: In summary, the metabolic differences identified here highlight the role of altered systemic metabolism and its relationship to fracture risk. Future investigations will determine if the identified metabolites serve as predictors of fracture in patients with T2D who are not Black.
PMID:42312207 | PMC:PMC13268917 | DOI:10.3389/fendo.2026.1777636
