Key Takeaways & Executive Findings
- •• • Serum ucOC levels were 0.82 ng/mL in T2DM patients versus 1.17 ng/mL in controls (30% reduction, p<0.05), indicating that undercarboxylated osteocalcin depletion is a hallmark of T2DM in the Chinese Han population; this suggests ucOC could serve as a diagnostic biomarker for early detection of insulin resistance. • • cOC levels were 12.19 ng/mL in T2DM patients versus 14.47 ng/mL in controls (16% reduction, p<0.05), and cOC exhibited a significant inverse correlation with HbA1c (8.95% in T2DM vs. control), implying that poor glycemic control directly impacts carboxylated osteocalcin levels, potentially linking bone health to glucose homeostasis. • • The ucOC/cOC ratio was 0.07 in T2DM patients versus 0.09 in controls (22% reduction, p<0.05), reflecting a shift in osteocalcin carboxylation status that may contribute to T2DM pathophysiology; this ratio could be a more sensitive marker than total OC for assessing metabolic dysfunction. • • The CC genotype at rs933489 was associated with lower ucOC levels in Chinese Han T2DM patients (p<0.05), identifying a genetic predisposition that could guide personalized risk assessment and therapeutic strategies targeting osteocalcin pathways in this population.
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Abstract
Type 2 diabetes mellitus (T2DM) is an endocrine metabolic disorder characterized by insulin secretion dysfunction and/or insulin resistance. Osteocalcin (OC), or bone γ-carboxyglutamic acid protein (BGP), is a bone matrix protein predominantly produced by osteoblasts. Vitamin K-dependent carboxylation converts OC into gamma-carboxyglutamic acid (Gla)-rich carboxylated osteocalcin (cOC), which binds to hydroxyapatite and can be decarboxylated to undercarboxylated osteocalcin (ucOC) under acidic conditions. While cOC influences bone formation and mineralization, ucOC regulates energy metabolism. OC enhances adiponectin production and insulin sensitivity; however, its relationship with diabetes incidence and glucose levels remains controversial. This study aimed to explore the associations between T2DM, serum OC levels (including cOC and ucOC), and OC gene polymorphisms in the Chinese Han population. T2DM patients and a healthy cohort, all of Han ethnicity, were categorized into a T2DM group (n = 456) and a control group (n = 224). Serum levels of cOC and ucOC were determined via enzyme-linked immunosorbent assay. Insulin sensitivity was assessed via homeostatic model assessment of insulin resistance (HOMA-IR). Pancreatic β-cell function was evaluated with HOMA-β. Nine SNPs in the OC gene were selected from the International HapMap Project database: rs12563631, rs2241106, rs2277872, rs2758605, rs1543294, rs1800247, rs2842880, rs759330, and rs933489. Genotyping was conducted via the SNaPshot technique. Pearson correlation and multiple linear regression analyses were performed. Compared with controls, T2DM patients presented significantly lower levels of ucOC (0.82 ng/mL), cOC (12.19 ng/mL), and ucOC/cOC ratio (0.07) (1.17 ng/mL, 14.47 ng/mL, and 0.09, respectively). Additionally, T2DM subjects had elevated BMI (25.06 kg/m2), HbA1c (8.95%), HOMA-IR (0.61), ALP (79.00 U/L), and TG (1.50 mM). Notably, cOC levels exhibit a significant inverse correlation with HbA1c, whereas no such correlation was observed for ucOC. The CC genotype at rs933489 is associated with lower ucOC levels in Chinese Han T2DM patients. These findings provide novel perspectives on the role of OC in T2DM pathophysiology.
1. Introduction
Type 2 diabetes mellitus (T2DM) affects over 500 million adults globally, with China bearing the largest burden. Despite advances in glucose-lowering therapies, a substantial proportion of patients fail to achieve glycemic targets, underscoring the need for novel biomarkers and therapeutic targets. Osteocalcin, a bone-derived protein, has emerged as a potential regulator of energy metabolism, but its role in T2DM remains contentious due to conflicting reports on serum levels and genetic associations. The carboxylation status of osteocalcin—specifically the ratio of undercarboxylated (ucOC) to carboxylated (cOC) forms—appears critical for its metabolic activity, yet clinical data in the Chinese Han population are scarce.
This study addresses the gap by systematically evaluating serum cOC and ucOC levels, along with nine single nucleotide polymorphisms (SNPs) in the osteocalcin gene, in a well-characterized cohort of 456 T2DM patients and 224 healthy controls. By integrating biochemical measurements with genetic profiling, we aim to clarify the relationship between osteocalcin carboxylation and T2DM, and to identify genetic variants that modulate ucOC levels. The findings could inform the development of early diagnostic markers and personalized interventions targeting bone-derived metabolic regulation.
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QI Luyue, WU Hong, LI Xiangqi, XU Yang, LIU Liangyong (2025). Osteocalcin Carboxylation/Undercarboxylation Levels and Gene Variants Associated with Type 2 Diabetes Mellitus in the Chinese Han Population. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025060
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Frequently Asked Questions
What is the mechanistic basis for the inverse correlation between cOC and HbA1c, and does it hold clinical significance for glycemic management?
The inverse correlation (p<0.05) suggests that chronic hyperglycemia, reflected by elevated HbA1c (8.95% in T2DM vs. controls), may suppress osteoblast function or alter vitamin K-dependent carboxylation. Clinically, this implies that improving glycemic control could restore cOC levels, potentially benefiting bone health. However, causality remains to be established; longitudinal studies are needed to determine whether cOC can serve as a surrogate marker for glycemic control.
How does the rs933489 CC genotype affect ucOC levels, and what are the implications for personalized risk assessment in T2DM?
The CC genotype at rs933489 was associated with significantly lower ucOC levels (p<0.05) in T2DM patients. This variant may impair osteocalcin carboxylation or secretion, reducing the metabolically active ucOC fraction. For personalized medicine, genotyping rs933489 could identify individuals at higher risk for ucOC deficiency, who might benefit from interventions such as vitamin K supplementation or lifestyle modifications to enhance osteocalcin function.
Given the cross-sectional design, what are the limitations in inferring causality between osteocalcin levels and T2DM, and how can future studies address them?
Cross-sectional data cannot establish temporal relationships; low ucOC may be a consequence rather than a cause of T2DM. Future longitudinal cohorts with repeated measures and Mendelian randomization using rs933489 as an instrumental variable could clarify causality. Additionally, mechanistic studies in osteoblast cultures under hyperglycemic conditions are needed to elucidate molecular pathways.
What are the technical challenges in standardizing ucOC and cOC assays for clinical use, and how does the ELISA used here perform?
The ELISA kit (TaKaRa) used in this study has acceptable sensitivity, but standardization across platforms remains a challenge due to differences in antibody specificity and sample handling. The observed 30% reduction in ucOC (0.82 vs. 1.17 ng/mL) is statistically significant, but clinical utility requires validation in larger, multi-ethnic cohorts. Pre-analytical factors such as fasting status and storage conditions must be controlled to ensure reproducibility.
Could targeting osteocalcin pathways be a viable therapeutic strategy for T2DM, and what are the potential pitfalls?
Preclinical studies suggest ucOC improves insulin sensitivity, but translating this to humans is complex. Systemic administration of ucOC may have off-target effects on bone mineralization. Alternative approaches, such as enhancing endogenous ucOC via vitamin K or modulating osteoblast activity, warrant investigation. However, long-term safety and efficacy data are lacking, and the risk of osteoporosis must be carefully balanced.
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