Reduced Serum Concentrations of Carboxylated and Undercarboxylated Osteocalcin Are Associated With Risk of Developing Type 2 Diabetes Mellitus in a High Cardiovascular Risk Population: A Nested Case-Control Study

Context and Objective: Because it has been suggested that osteocalcin (OC), an osteoblast-derived hormone, is a new link between bone and glucose metabolism, we tested whether serum carboxylated osteocalcin (cOC) and undercarboxylated osteocalcin (ucOC) levels are independently associated with the development of type 2 diabetes in subjects at high cardiovascular risk. Design, Setting, and Participants: A prospective, nested case-control study was conducted using data from the Prevencion con Dieta Mediterranea (PREDIMED) study. We included 153 case subjects with newly diagnosed diabetes and 306 individually matched control subjects free of diabetes identified during a mean 5-year follow-up. Conditional logistic regression models were used to estimate matched odds ratios for incident diabetes according to categories of both forms of OC measured by ELISAs. Results: Baseline serum concentrations of both forms of OC were significantly lower in case subjects than in control subjects. In subjects with incident cases of diabetes, concentrations of cOC, but not of ucOC, were inversely and significantly associated with homeostasis model assessment of insulin resistance levels (beta = -0.335) and with fasting glucose concentrations (beta = -0.044) in control subjects, independent of other relevant confounders. In the conditional logistic model that took into account the matching factors, the odds ratios for diabetes incidence in the lowest vs the highest tertile of cOC and ucOC were 2.03 (95% confidence interval, 1.32-3.13) and 1.88 (1.23-2.85), respectively. Further adjustment for family history of diabetes, lifestyle, and other confounding factors did not appreciably change the magnitude of these associations. Conclusion: In a population at high cardiovascular risk, low concentrations of serum cOC and ucOC were strongly associated with an increased risk of incident diabetes.