Type 2 diabetes mellitus (T2DM) is rising globally, with a disproportionate burden in low- and middle-income countries. The 10th-edition International Diabetes Federation (IDF) Atlas estimates that approximately 589 million adults were living with diabetes in 2024 and projects an increase to about 853 million by 2050, highlighting the urgency for improved early detection and risk-stratification strategies 1. Within India, nationally representative data from the ICMR–INDIAB study indicate an overall diabetes prevalence of 11.4 %, equating to roughly 101 million people with diabetes and another 136 million with pre-diabetes—an epidemiologic landscape that demands sensitive biomarkers linked to metabolic control and complications 2.

In parallel with this epidemiologic surge, there is growing recognition that bone functions as an active endocrine organ that interfaces with systemic energy homeostasis. Recent evidence underscores a bone–energy-metabolism crosstalk, wherein osteoblast- and osteocyte-derived factors influence glucose utilization and lipid handling in peripheral tissues 3,4. This paradigm recasts skeletal biology not merely as a passive target of metabolic disease but as a regulatory hub capable of providing biomarkers for metabolic-risk assessment and informing novel therapeutic interventions in T2DM 3,4.

Among bone-derived signals, osteocalcin (OC)—particularly its undercarboxylated form (ucOC)—has emerged as a hormone with metabolic effects, enhancing pancreatic β-cell proliferation, stimulating insulin secretion, and improving insulin sensitivity in skeletal muscle and adipose tissue 5,6. Both human and experimental studies support these roles; however, the magnitude and clinical utility of osteocalcin–glycaemia associations vary across populations and cardiometabolic conditions, underscoring the need for population-specific investigations to ascertain its translational relevance, particularly in regions with a dual burden of T2DM and metabolic-bone disturbances 5,6.

Vitamin D is likewise a key endocrine regulator with wide-ranging effects on glucose and lipid metabolism. Observational studies consistently link lower serum 25-hydroxyvitamin D [25(OH)D] levels with higher insulin resistance and adverse lipid profiles 7. Meta-analytical evidence further suggests that vitamin D supplementation can lower fasting glucose, HbA1c, HOMA-IR, and fasting insulin in patients with T2DM, especially in those who are deficient or poorly controlled 8. In India, vitamin D deficiency is highly prevalent, with studies documenting > 50 % deficiency in both urban and rural cohorts, underlining its relevance to metabolic-risk evaluation 9,10,11.

Parathyroid hormone (PTH), intricately linked to calcium–phosphate balance and vitamin D status, may also contribute to energy regulation. Clinical evidence suggests that higher PTH levels are associated with worse glycaemic indices, β-cell stress, and insulin resistance 12. Yet, PTH is seldom examined alongside osteocalcin and vitamin D in relation to both glycaemic and lipid parameters—particularly in South-Asian cohorts, where the combination of diabetes, vitamin D deficiency, and dyslipidaemia is disproportionately high 2,9.

Despite the growing body of literature on individual endocrine axes, an integrative analysis that simultaneously evaluates osteocalcin, vitamin D, and PTH in the context of T2DM remains scarce. Examining their combined relationships with both glycaemic-control parameters (fasting plasma glucose, HbA1c) and lipid variables (triglycerides, LDL-C, HDL-C, and total cholesterol) is particularly relevant for Indian populations, where multiple metabolic derangements converge. By quantifying these endocrine markers concurrently, the present study aims to (i) delineate the bone–mineral–metabolic interface in T2DM, (ii) identify clinically tractable biomarkers that complement conventional indices, and (iii) generate population-specific evidence that could support early detection and enhanced risk-stratification strategies in diabetes care 1,2,3,4,5,6,7,8,9,10,11,12.

The present study assessed the interrelationships of serum osteocalcin, vitamin D₃, and parathyroid hormone (PTH) concentrations in patients with type 2 diabetes mellitus (T2DM) and their association with glycaemic and metabolic parameters. Our findings illuminate the endocrine cross-talk between bone metabolism and glucose homeostasis, underscoring the potential role of bone-derived hormones and the calcium–vitamin D–PTH axis in diabetes pathophysiology. Osteocalcin—a peptide hormone secreted by osteoblasts—has been proposed to modulate glucose metabolism by enhancing pancreatic β-cell proliferation, insulin secretion, and insulin sensitivity 26. In our cohort, osteocalcin concentrations neither differed significantly across vitamin D₃ or PTH strata nor correlated strongly with glycaemic indices, suggesting that its role in T2DM may be contingent on other metabolic factors. Previous studies have reported an inverse association between osteocalcin and fasting glucose or HbA₁c, supporting its protective role in glucose homeostasis 27,28. However, inconsistencies across investigations, including ours, may reflect population heterogeneity, treatment regimens, and vitamin D status, all of which influence bone turnover. International studies generally demonstrate inverse osteocalcin–glycaemia relationships, whereas findings in Indian cohorts have been variable: a study of central-Indian men found osteocalcin to be negatively correlated with fasting plasma glucose, insulin resistance, and triglycerides 29, while another central-Indian cohort reported lower osteocalcin levels in T2DM and an inverse association with HbA₁c and HOMA-IR 30. Discrepancies may stem from differences in osteocalcin assays (total vs. under-carboxylated), sample handling, vitamin K status, ethnicity, medication use, and sample size.

A principal observation of our study is the strong inverse association between serum vitamin D₃ and PTH. Patients with vitamin D deficiency (< 20 ng/mL) consistently exhibited elevated PTH, reinforcing the well-established physiological role of vitamin D in suppressing PTH secretion via calcium regulation 30. These findings align with reports that vitamin D deficiency in T2DM is frequently associated with secondary hyperparathyroidism and impaired glucose metabolism 31. Although vitamin D supplementation has been shown to improve glycaemic indices, results remain equivocal 32. Participants with elevated PTH (> 65 pg/mL) displayed significantly higher fasting blood glucose and HbA₁c than those with normal PTH, implying that hyperparathyroidism may contribute to sub-optimal glycaemic control in T2DM. Experimental data indicate that excess PTH can impair insulin signalling and promote insulin resistance by altering intracellular calcium handling 33. Additionally, hyperparathyroidism has been linked to dyslipidaemia, hypertension, and heightened cardiovascular risk in diabetic populations 34.

Correlation analyses revealed that HbA₁c was inversely correlated with vitamin D₃ and positively correlated with PTH in both T2DM and control groups, emphasising the bidirectional link between mineral metabolism and glycaemic regulation. Prior studies suggest that vitamin D deficiency may reduce insulin secretion through diminished vitamin D-receptor activation in pancreatic β-cells, whereas elevated PTH may exacerbate insulin resistance 35,36. Notably, osteocalcin did not correlate significantly with vitamin D₃ or PTH in our cohort, indicating that its regulation in T2DM may be independent of the classical vitamin D–PTH axis, consistent with other reports 37.

The novelty of our work lies in the integrated evaluation of osteocalcin, vitamin D₃, and PTH within a single T2DM cohort, enabling delineation of their independent and interactive contributions to glycaemic control. Our results suggest that osteocalcin is unlikely to serve as a reliable marker of glycaemic control in Indian T2DM patients, whereas vitamin D deficiency and secondary hyperparathyroidism are strongly linked to poor glycaemic status. These observations underline the potential benefit of routine screening for—and correction of—vitamin D deficiency as part of comprehensive diabetes-management strategies.

The present study provides significant insight into the endocrine interactions among serum osteocalcin, vitamin D, and parathyroid hormone (PTH) in glycemic and lipid metabolism among patients with type 2 diabetes mellitus (T2DM). Our findings demonstrate a robust inverse correlation between vitamin D₃ and PTH, suggesting that vitamin D deficiency and secondary hyperparathyroidism are significant contributors to poor metabolic regulation in T2DM. Patients with vitamin D insufficiency exhibited poorer glycemic control and adverse lipid profiles, highlighting the critical role of vitamin D in glucose-lipid homeostasis. Interestingly, osteocalcin, although biologically linked to insulin sensitivity and β-cell function, was not directly associated with glycaemic or lipid parameters in this cohort. These findings underscore the complexity of osteocalcin’s involvement in human glucose metabolism and suggest that its clinical relevance may be influenced by additional regulatory pathways, such as vitamin D–PTH interactions and the inherent metabolic heterogeneity observed in T2DM. Overall, our results emphasize that maintenance of optimal vitamin D levels may represent a feasible and cost-effective approach to attenuate glycaemic instability and dyslipidaemia in individuals with T2DM.

ADA: American Diabetes Association; ATP Adenosine triphosphate; BMI Body mass index; CHOD-PAP Cholesterol oxidase–phenol amino-antipyrine (enzymatic assay); CI Confidence interval; CLIA Chemiluminescence immunoassay; CV Coefficient of variation; CTRI Clinical Trials Registry – India; ELISA Enzyme-linked immunosorbent assay; FBG Fasting blood glucose; FBS Fasting blood sugar (synonym of FBG); FPG Fasting plasma glucose; HbA1c Glycated haemoglobin A1c; HDL-C High-density lipoprotein cholesterol; HOMA-IR Homeostatic Model Assessment of Insulin Resistance; HPLC High-performance liquid chromatography; ICMR Indian Council of Medical Research; IDF International Diabetes Federation; INDIAB India Diabetes (ICMR-INDIAB) study; IQR Interquartile range; LDL Low-density lipoprotein; LDL-C Low-density lipoprotein cholesterol; NADH Nicotinamide adenine dinucleotide (reduced form); OC Osteocalcin; PPBS Post-prandial blood sugar; PTH Parathyroid hormone; RBG Random blood glucose; SD Standard deviation; SOP Standard operating procedure; SPSS Statistical Package for the Social Sciences; STROBE Strengthening the Reporting of Observational Studies in Epidemiology; T2DM Type 2 diabetes mellitus; TG Triglycerides; ucOC Undercarboxylated osteocalcin.

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