Osteocalcin: A clue to insulin resistance in obese children

Could bones hold clues to early metabolic problems? Researchers uncover a surprising association between osteocalcin and insulin resistance in children with obesity, even before glucose tolerance becomes impaired.

Study: Role of Osteocalcin in the Regulation of Glucose Metabolism in Children and Adolescents with Obesity. Image credit: Pixel-Shot/Shutterstock.com

A recent exploratory study in the journal Nutrients investigated the relationship between osteocalcin (OC), a bone-derived hormone, and glucose metabolism in children and adolescents with obesity. Higher serum OC concentrations were associated with higher fasting insulin levels and greater estimated insulin resistance, despite preserved glucose tolerance.

How bone-derived osteocalcin may influence glucose metabolism

Childhood obesity is associated with an increased risk of metabolic problems, including insulin resistance, abnormal blood lipid levels, and impaired glucose regulation. These changes can begin early in life, sometimes before blood glucose levels become abnormal. However, the biological mechanisms linking obesity to metabolic dysfunction during childhood and adolescence are not yet fully understood.

Researchers are increasingly exploring the role of bone in metabolic health. Beyond providing structural support, bone may also act as an endocrine organ, releasing substances that influence how the body regulates energy and glucose.

One such substance is osteocalcin (OC), a protein produced by bone-forming cells called osteoblasts. Traditionally used as a marker of bone formation, osteocalcin has attracted interest for its potential role in insulin secretion and sensitivity. Experimental research has particularly focused on undercarboxylated osteocalcin (ucOC), one of its circulating forms, which may influence glucose metabolism through hormonal signaling.

This relationship could be particularly relevant to insulin resistance, a condition in which the body’s cells become less responsive to insulin. To compensate, the pancreas produces more insulin to maintain normal blood glucose levels, meaning insulin resistance can develop before glucose tolerance becomes impaired.

Against this backdrop, researchers investigated whether circulating osteocalcin levels were associated with insulin resistance and other clinical and biochemical measures in children and adolescents with obesity who maintained normal glucose tolerance.

Researchers examine osteocalcin and insulin resistance in 33 children

The researchers conducted a single-center retrospective study at the Regional Reference Center for Pediatric Obesity, A.O.U. G. Martino, in Messina, Italy. Clinical, auxological, and biochemical data were collected from medical records.

The study included 33 children and adolescents with obesity: 13 males and 20 females, with a mean age of 10.4 years. Participants were aged 5.3–15.5 years, and all had a body mass index (BMI) at or above the 95th percentile for age and sex.

Measurements included weight, height, BMI, bone age, and waist-to-hip ratio (WHR). Biochemical assessments covered fasting glucose and insulin, lipid profiles, liver enzymes, uric acid, thyroid function, insulin-like growth factor 1, and markers of bone and mineral metabolism, including calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, C-terminal telopeptide of type I collagen (CTX), and OC.

Insulin resistance was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR), with the threshold set at >2.5. Participants exceeding this threshold underwent further evaluation of glucose and insulin concentrations during an oral glucose tolerance test (OGTT).

Higher osteocalcin levels linked to greater insulin resistance

The participants had a mean BMI of 32.01 ± 5.9 kg/m², mean excess weight of 173.63 ± 31.13%, and mean waist-to-hip ratio of 0.934 ± 0.07.

Twenty-two participants had insulin resistance, defined by both high HOMA-IR and an abnormal insulin response curve. Despite this, the researchers reported normal glucose tolerance in all participants, with none meeting the diagnostic criteria for type 2 diabetes.

Mean fasting glucose was 88 mg/dL, mean fasting insulin was 25 μU/mL, and mean serum OC concentration was 112 ng/mL. The mean HOMA-IR was 5.6.

Exploratory analyses revealed moderate positive correlations between serum OC and fasting insulin, and between OC and HOMA-IR, but not with other parameters examined. However, these analyses were not adjusted for multiple comparisons, and the small sample prevented robust adjustment for potential confounders.

These findings suggest that higher OC concentrations may be associated with greater estimated insulin resistance and hyperinsulinemia in this cohort, even before overt abnormalities in glucose tolerance develop.

New findings contrast with earlier osteocalcin research

The positive association observed in this study differs from findings in several adult populations with established type 2 diabetes (T2DM). For instance, a weak negative correlation between OC and HOMA-IR was observed in Chinese adults with type 2 diabetes mellitus in one study.

Conversely, another study showed a negative association between OC and insulin resistance but only when assessed using the triglyceride-glucose index, and not HOMA-IR. These contrasting findings raise the possibility that the relationship between OC and insulin resistance differs across stages of metabolic dysfunction, although longitudinal research is needed to establish whether it changes over time.

Pediatric studies have also produced conflicting results, with some investigators reporting negative and others no associations between OC and HOMA-IR, fasting insulin, or glucose in obese children. Undercarboxylated osteocalcin (ucOC) has also failed to show significant associations with HOMA-IR after adjustment for adiposity.

Among children with type 1 diabetes (type 1 diabetes mellitus“>T1DM), one study reported an inverse association between OC and glycated hemoglobin shortly after T1DM onset. Another study at the authors’ center found a positive correlation between OC and stimulated C-peptide (a marker of insulin secretion) in children and adolescents with newly diagnosed T1DM.

Proposed biological mechanisms include crosstalk between osteoblasts and pancreatic beta cells, whereby insulin signaling in osteoblasts promotes OC production, while OC influences insulin secretion. However, the pathways underlying these associations remain incompletely understood. Differences between studies may reflect variations in metabolic status, age, pubertal development, adiposity, inflammatory factors, OC forms measured, and study design.

The authors suggest that elevated OC in children with obesity and insulin resistance might reflect a metabolic response during early dysregulation of energy metabolism. However, this remains a hypothesis, given the observational design.

Small sample and unmeasured confounders limit conclusions

The study has several limitations that reduce its generalizability. The retrospective, observational, single-center design may introduce selection and information bias and precludes causal inference. The small sample limits statistical power and prevents stratified or robust multivariable analyses, leaving residual confounding possible.

The cross-sectional design also prevents assessment of the temporal relationship between OC levels and insulin resistance. Potential confounders include pubertal status, physical activity, dietary habits, body composition, and psychological factors such as stress and anxiety. These factors may influence bone and metabolic health, particularly during growth and puberty.

The researchers applied a single HOMA-IR threshold of greater than 2.5 across the cohort. Although used previously among children, this ignores possible variations in HOMA-IR with age, sex, and pubertal development. All participants had obesity but maintained preserved glucose tolerance, and the data came from a specialized pediatric center. The results therefore may not generalize to children with other weight and metabolic characteristics.

Larger, longitudinal studies with more comprehensive assessments of circulating OC forms and beta-cell function are needed to understand the temporal relationship between OC and beta-cell function, and to determine the value of OC as an early biomarker of metabolic dysfunction.

Bone hormone findings highlight possible early metabolic changes

In children and adolescents with obesity, higher serum OC levels were associated with higher fasting insulin levels and greater estimated insulin resistance despite preserved glucose tolerance. The authors hypothesized that the relationship between OC and metabolic health might vary with metabolic status and developmental stage.

The findings suggest a potentially complex relationship between bone metabolism and early metabolic dysfunction. However, this preliminary evidence cannot establish causality or determine whether OC plays a protective or adaptive role. It does not establish that OC compensates for an early decline in beta-cell function. Larger longitudinal studies are needed to clarify the underlying mechanisms and potential clinical significance.