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Bone has traditionally been considered a passive organ, serving only as a scaffold for other organs and the entire body. However, over the past few years, an increasing number of studies have highlighted its function as an endocrine organ regulating energy and adipose tissue metabolism by producing undercarboxylated osteocalcin (ucOC). In mice, ucOC administration through different routes has been explored for its potential as a therapeutic or preventive method for reducing adipocyte size and normalising glucose homeostasis. The discovery of these endocrine properties of ucOC in rodent models for obesity prevention and treatment necessitates evaluating the association of ucOC with insulin resistance and obesity-related parameters in humans. This study aimed to investigate the association between total osteocalcin and ucOC, which is proposed as the active form in rodent models, with glucose metabolism markers, insulin resistance, and obesity-related parameters (i.e. Haemoglobin A1c, fasting glucose, and insulin resistance evaluated by homeostasis model assessment) in individuals who are overweight or obese. This study concluded the possible correlation of ucOC, with insulin resistance and highlights that waist/hip ratio can be a predictor of ucOC.
Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
*Address all correspondence to: venera.berisha@uni-pr.edu
1. Introduction
The number of people suffering from metabolic syndrome (MetSy) is increasing globally. MetSy is a group of risk factors for various conditions, including insulin resistance, hypertension, high triglyceride levels, low high-density lipoprotein levels, and abdominal obesity, where the key problem seems to be insulin resistance. These factors put individuals at a higher risk of developing cardiovascular disease and type 2 diabetes (T2D) [1].
Recent studies have suggested the existence of a close relationship between bone metabolism and the metabolism of energy, glycaemia, and insulin, mediated by osteocalcin (OC) [2, 3]. Endocrinologists have traditionally considered bone an organ, where the actions of only classic hormones (such as steroids, parathyroid hormone, and calcitonin) were known. Bones were considered merely a part of the skeleton, a supportive system. However, results from research in the past few decades have demonstrated that bone mass is also regulated by fat through leptin, which acts upon the brain, and downstream through the hypothalamic relay and sympathetic nervous system [4, 5, 6, 7]. Based on these findings, from an endocrine perspective, it can be speculated that there is a feedback mechanism. Indeed, research and experiments involving rodent models suggest a new possible role for bone by producing OC, which acts as a hormone that influences insulin production and sensitivity, glucose utilisation, and energy expenditure [6, 7, 8]. Reviews of these findings have been published [6, 7, 8, 9, 10, 11].
OC (also called bone γ-carboxyglutamic acid protein) is a bone protein secreted by osteoblasts consisting of 46–50 residues (Figure 1) [6, 7, 12] that undergoes posttranslational modification by vitamin K dependent γ-carboxylation of three glutamic acid residues [6, 7, 13]. Undercarboxylated osteocalcin (ucOC), which is the OC form with a lower binding affinity to bone, has fewer than three carboxylated residues [5, 6, 7]. In human serum, both forms can be found and measured. OC, until recently, was used only as a useful marker of bone formation. It is expressed by mature osteoblasts, binds strongly to hydroxyapatite, is stored in the bone matrix, and is released into the circulation [5, 6, 7].
Figure 1.
Osteocalcin structure [6, 7, 8]. Three glutamic acid residues are present at positions 17, 21, and 24, and a disulphide bridge is present between residues 23 and 29.
Mutant mice without osteocalcin (OC _/_ mice) show no remarkable bone phenotype but appear hyperglycaemic and have increased visceral fat [6, 7, 14]. On the other hand, mutant mice with deletion of the Esp gene (Esp _/_ mice), a gene encoding a receptor-like protein (osteotesticular protein tyrosine phosphatase [OST-PTP]), resulting in a phenotype opposite that of OC _/_ mice. Esp _/_ mice present with increased pancreatic islet size, β-cell number, and circulating insulin levels; increased insulin sensitivity despite hypoglycaemia; decreased visceral fat mass; increased expression of insulin target genes in the liver and muscle; increased energy expenditure; and unaffected food intake [2, 6, 7].
In ex vivo experiments, OC stimulates insulin expression in β cells and adiponectin, an adipokine whose overexpression enhances insulin sensitivity [6, 7, 15]. Insulin production and insulin sensitivity have been indicated to be enhanced by either OC addition or OC overproduction by osteoblasts. In vivo treatment of normal mice with non-γ-carboxylated OC generated by bacterial expression has resulted in increased pancreatic β-cell numbers, insulin secretion, energy expenditure, and insulin sensitivity, so it has the opposite effect on metabolism as that in OC _/_ mice [6, 7, 16]. Hence, Esp _/_ mice are also protected from diabetes, similar to treated mice with non-γ-carboxylated OC; alternately, bone-specific overexpression of OST-PTP results in a phenotype identical to that of OC _/_ mice. Therefore, the hypothesis has been made that OST-PTP is responsible for inactivating OC through γ-carboxylation [3, 6, 7].
It can be summarised that OC can act and be considered a hormone. However, its regulation is not yet fully understood, and receptor-like proteins, such as OST-PTP, may be involved in its signalling pathways, which are still unclear [6, 7]. The initial, definitive information about the role of OC, as a circulating hormone and especially its undercarboxylated fraction, in energy metabolism and particularly in the regulation of insulin secretion came from studies in mouse models where the experimental production of OC was either deactivated or increased [6, 7].
A similar OST-PTP as in mice has not been identified in humans. However, the OC level in human blood appears to be significantly lower in individuals with diabetes than in nondiabetic controls, and the level is inversely related to adiposity and blood glucose levels [6, 7, 17, 18]. Even in postmenopausal women, the OC level was significantly lower in subjects with T2D than in nondiabetic controls [19]. In a study that evaluated the effects of a hypocaloric diet and exercise, OC levels were positively associated with insulin sensitivity and negatively associated with triglyceride levels in a fasting state [20]. Serum OC level has been demonstrated to be associated with glucose metabolism and other atherosclerosis parameters in patients with T2D [21, 22]. Even in gestational diabetes, a higher OC level is observed compared to pregnancies with normal glucose levels [23]. In individuals with poorly controlled diabetes, only after 1 month of treatment and good glycaemic control was an increase in OC levels observed, while serum adiponectin did not show a difference before and after glycaemic control. However, the baseline level of adiponectin appears to predict the beneficial bone response [24]. Overall, in most studies, it can be concluded that the OC level increases in individuals with T2D after glycaemic control improvement [6, 7, 25, 26, 27].
Most publications on OC in humans were designed to study the effect of diabetes on bone remodelling and then, after the discovery of the endocrine effect, to retrospectively analyse the OC level of patients with diabetes [20, 21]. They were not initially designed to assess the effect of OC on insulin resistance or energy metabolism. Therefore, the exact role of OC in regulating insulin resistance cannot be conclusively determined yet and remains to be clarified.
Moreover, most previous clinical studies that have investigated the possible metabolic effects of OC did not differentiate total osteocalcin (TOC) from ucOC, which in rodents has been indicated to be the active form with metabolic effects. Experimental data has concluded that ucOC is involved in metabolism [3, 11]. Additionally, recent data from healthy children suggest a similar state in humans [28]. Studies in humans have indicated that improved glycaemic control increases the TOC level, but this does not necessarily mean that the same effect occurs for ucOC. Additional studies on the ucOC level are needed to clarify the effects of glycaemic control and insulin resistance improvement on this suggested hormone and vice versa.
TOC has been found to correlate with a decrease in insulin resistance and stimulate the production of insulin from the pancreas [12, 29]. Serum OC levels correlate with body mass index (BMI), C-reactive protein, insulin, and waist circumference [30]. OC levels have shown a significant negative correlation with insulin resistance (homeostasis model assessment for insulin resistance [HOMA-IR]) and waist/hip ratio [31]. Thus, serum OC levels in MetSy and insulin resistance could potentially be a new area to explore therapeutically. However, its role in clinical practice, especially the influence of the undercarboxylated form of this hormone on insulin sensitivity and vice versa, needs to be established.
This study, for the first time, aimed to investigate the relationship between not only TOC but also its supposed active fraction, ucOC, and insulin resistance as a companion occurrence of overweight and obesity in individuals without any medical treatment affecting their OC levels [32]. Furthermore, the study aimed to determine the correlation of both forms of OC with insulin resistance markers, glucose metabolism, and other obesity-related parameters in overweight and obese individuals [32].
In a cross-sectional study, 123 consecutive persons, female (n = 82) and male (n = 41), with overweight and obesity (WHO criteria) [33] and aged 19–79 years were evaluated. The exclusion criteria were as follows: any pharmacologic treatments (not to interfere with study results), current or former smoking, pregnancy, and lactation, a history of type 1 diabetes mellitus, renal disease or renal failure, severe liver disease, HIV infection, known haematological diseases, eating disorders, or any psychiatric illness, functional thyroid disease, a history of bariatric surgery, malignancy, and metabolic bone disease.
Patient data were collected at Endomedica Polyclinic, Prishtina, Kosovo, between February 2022 and February 2023. The study was conducted in accordance with the Declaration of Helsinki and approved by the Committee of Ethics of the Faculty of Medicine, University of Prishtina, Kosovo (project identification code: 2679).
2.1 Clinical data: patient history
The data collected included answers to questions about the duration of overweight and obesity, family history, drug treatment, smoking, physical activity, and signs of other diseases or obesity complications. A physical examination was performed for each patient, including blood pressure measurements and measurements of weight, height, waist circumference, and hip circumference. Waist/hip ratio and BMI (weight [kg] divided by height2 [m]) were calculated.
Blood was taken after a sober period at night. Commercial kits were used for biochemical parameters, and standard methods were recommended for routine biochemical tests. Fasting glucose, fasting insulin, Haemoglobin A1c (HbA1c), TOC, and ucOC levels were measured. Insulin resistance was assessed at the basal state—estimated by the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), estimated steady state of β-cell function (HOMA%B), and insulin sensitivity (HOMA%S) [34] and calculated, using a downloaded calculator, from fasting blood glucose and fasting insulin level [35].
2.3 Statistical analyses
Median and interquartile range as variable summary parameters are used. A comparison between groups was made with the independent samples using the Mann-Whitney U test. The correlation between variables was tested with the Spearman correlation test, and linear regression tests were used to analyse the dependent variables: TOC and ucOC.
The median age of the participants was 38 years (interquartile range: 30–45 years), and as shown in Table 1, no statistically significant difference was found between men and women (p > .05). Men were found to have higher levels of BMI, waist/hip ratio, HbA1c, Fasting blood glucose (FBG), insulin, β-cell function (HOMA%B), and insulin resistance (HOMA-IR) compared to women (p < .05; Table 2). However, women had higher levels of HOMA%S, TOC, and ucOC compared to men (p < .05). About 32% of the men and 19% of the women in the study sample were in the obese class 3 category (Figure 2). Approximately 13% of the women and 15% of the men included in the study had hypertension (Figure 3). In addition, 8% of women and 12% of men had T2D (Figure 4).
Total N = 123
F n = 82
M n = 41
p
Median
IQR
Median
IQR
Median
IQR
Age (years)
38.00
30.00
45.00
38.00
29.00
49.25
36.00
30.50
43.50
.232
BMI (kg/m2)
33.60
29.40
38.00
31.85
28.68
36.38
36.50
32.65
41.45
.001
Waist/hip ratio
1.00
0.90
1.10
0.90
0.90
1.00
1.10
1.10
1.30
<.0001
HbA1c (%)
5.40
5.06
6.09
5.20
4.90
6.00
5.80
5.21
6.25
.008
FBG (mmol/L)
5.40
5.00
5.90
5.30
4.92
5.83
5.72
5.20
6.10
.012
Insulin (μIU/L)
14.90
8.20
27.20
11.60
6.28
19.43
23.90
14.83
48.95
<.0001
HOMA%B
122.30
84.60
181.30
108.95
79.70
153.45
160.40
101.60
239.60
<.0001
HOMA%S
50.10
27.50
92.60
67.00
39.33
123.35
33.40
16.40
51.20
<.0001
HOMA-IR
2.00
1.08
3.60
1.52
0.80
2.53
2.99
1.95
6.10
<.0001
TOC (μg/L)
15.00
11.85
22.51
18.05
12.50
29.80
13.20
9.89
16.85
.001
ucOC (ng/mL)
1.12
0.65
1.60
1.44
0.98
2.09
0.58
0.36
1.02
<.0001
Table 1.
Comparison of measured parameters for both male and female patients. BMI—body mass index; HbA1c—Haemoglobin A1c; FBG—fasting blood glucose; HOMA%S—insulin sensitivity; HOMA%B—estimated steady state of β-cell function; HOMA-IR—insulin resistance.
Age
BMI
Waist/hip ratio
HbA1c
FBG
Insulin
β-cell function
HOMA%S
HOMA-IR
TOC
ucOC
Age
r
1.000
.181
.090
.077
.245
.246
.110
−.268
.266
−.210
−.121
p
.044
.320
.399
.006
.006
.228
.003
.003
.018
.180
BMI
r
1.000
.432
.499
.343
.559
.397
−.558
.557
−.356
−.458
p
.000
.000
.000
.000
.000
.000
.000
.000
.000
Waist/hip ratio
r
1.000
.247
.333
.600
.424
−.595
.594
−.580
−.803
p
.006
.000
.000
.000
.000
.000
.000
.000
HbA1c
r
1.000
.443
.385
.053
−.419
.417
−.222
−.235
p
.000
.000
.558
.000
.000
.014
.009
FBG
r
1.000
.368
−.174
−.428
.425
−.206
−.248
p
.000
.054
.000
.000
.022
.006
Insulin
r
1.000
.777
−.993
.994
−.600
−.762
p
.000
.000
.000
.000
.000
HOMA%B
r
1.000
−.719
.721
−.440
−.610
p
.000
.000
.000
.000
HOMA%S
r
1.000
−1.000
.603
.751
p
.000
.000
.000
HOMA-IR
r
1.000
−.602
−.751
p
.000
.000
TOC
r
1.000
.716
p
.00
ucOC
r
1.000
p
Table 2.
Correlations of measured parameters. BMI—body mass index; HbA1c—Haemoglobin A1c; FBG—fasting blood glucose; HOMA%S—insulin sensitivity; HOMA%B—estimated steady state of β-cell function; HOMA-IR—insulin resistance; TOC—total osteocalcin; ucUC—undercarboxylated osteocalcin.
Figure 2.
Distribution based on body mass index.
Figure 3.
The prevalence of hypertension among the study participants.
Figure 4.
The prevalence of diabetes among the study participants.
We found a low negative correlation of TOC with age, BMI, FBG, and HbA1c and a medium negative correlation with waist/hip ratio, insulin, β-cell function, and insulin resistance (p < .05). Furthermore, there was a medium correlation of TOC with HOMA%S (p < .05).
We found a low negative correlation of ucOC with FBG and HbA1c and a medium negative correlation with BMI and HOMA%B. However, ucOC was negatively correlated with insulin (Figure 5), and we found a very strong negative correlation between ucOC and waist/hip ratio (Figure 6). In addition, there was a strong positive correlation between ucOC and HOMA%S (p < .05). Multiple linear regression analyses indicated that age, waist/hip ratio, and HOMA%S are significant predicting factors for TOC, and according to the results, waist/hip ratio can predict ucOC (Table 3).
Figure 5.
Negative correlation between undercarboxylated osteocalcin and insulin.
Figure 6.
Strong negative correlation between undercarboxylated osteocalcin and waist/hip ratio.
Total osteocalcin
Undercarboxylated osteocalcin
B (95% CI)
P
B (95% CI)
P
Age
−0.127 (−0.245 to −0.010)
.034
—
—
Waist/hip ratio
−21.254 (−29.654 to −12.855)
<.0001
−2.506 (−3.137 to −1.875)
<.0001
HOMA%S
0.069 (0.040–0.097)
<.0001
0.013 (0.004–0.022)
.006
Insulin
—
—
0.012 (0.10–0.015)
<.0001
Table 3.
Correlation of total osteocalcin (TOC) and undercarboxylated osteocalcin (ucOC) with age, waist/hip ratio, homeostasis model assessment for insulin sensitivity (HOMA%S) value, and insulin level.
The knowledge that ucOC secreted from bone regulates glucose metabolism dates back to studies by the Karsenty group—which generated, for the first time, rodent models without OC and revealed that these mutant OC-null mice accumulated abnormal amounts of visceral fat and exhibited severe glucose metabolism impairments [6, 7, 13, 36]. Because ucOC is an osteoblast-produced protein that enters the general circulation during bone remodelling [12, 36], it was speculated that ucOC is a hormone.
Studies with genetically modified rodent models have revealed that β cells in the pancreas are one of the major targets of ucOC as a hormone [36]. In OC _/_ mice, all the effects are reduced, including insulin secretion into the circulation; islet number; β-cell area, mass, and proliferation; and pancreatic insulin content [6, 7, 36]. In contrast, mice deficient in OST-PTP (Esp _/_ mice) exhibit the opposite phenotype and enhanced growth factor-mediated signalling in osteoblasts, thereby representing a gain-of-function model for ucOC [6, 7, 36].
Subsequent studies have highlighted that ucOC stimulates insulin gene expression [13] and functions as an insulin secretagogue [36, 37]. In addition to its effect on pancreatic cells, ucOC indirectly promotes insulin secretion by stimulating the secretion of glucagon-like peptide 1 from the small intestine [38]. This sequential hormonal work initiated by ucOC and then mediated by glucagon-like peptide 1 was proposed to be called a bone gut metabolism flow [36, 39].
To close the loop between bone and the pancreas, two independent groups demonstrated that insulin signalling in osteoblasts increases ucOC [36, 38, 40]. Moreover, infusion of ucOC for 2 weeks improved insulin sensitivity, and further experiments in animal models have demonstrated that insulin signalling in osteoblasts increases bone formation and, most importantly, OC production [36, 40]. Moreover, insulin signalling promotes OC decarboxylation, resulting in the release of circulating ucOC [36, 38].
Therefore, it was suggested that there is a regulatory loop between ucOC and insulin: insulin signalling in osteoblasts—which favours ucOC activity by promoting bone remodelling and, in turn, increases ucOC in the circulation. Increased ucOC levels then promote insulin production, secretion, and insulin sensitivity [36, 38, 40].
Afterwards, the next question centred on the applicability of ucOC’s beneficial effects. ucOC administration via various routes to obese or even normal rodent models has been experimented with for eventual therapeutic or preventive effects [16, 36, 41]. Long-term oral administration even reduced adipocyte size in mice [36, 42].
As for the endocrine function of ucOC in humans, the role of OC in energy metabolism and insulin resistance has been examined in some cross-sectional and observational studies [2, 20, 36, 43, 44, 45, 46, 47], indicating that serum OC and/or ucOC negatively correlate with blood glucose level, insulin level, insulin resistance, and obesity [2, 20, 36, 43, 44, 45, 46] and are positively associated with serum adiponectin and insulin production [21, 36, 43, 45, 47]. The active form of OC has been considered a potentially promising biomarker to classify cardiovascular risk and predict T2D prevalence in the MetSy population, especially for those without prevalent T2D [48].
Results from recent studies have indicated sex differences in the metabolic effect of ucOC, and Yasutake et al. showed a possible sex difference in rodent models in the effect of ucOC on glucose homeostasis [36, 42]. ucOC administered orally improved glucose homeostasis in female mice but did not have the same effect in males by causing glucose and insulin intolerance [36, 42]. In humans, decreased ucOC levels were found to be associated with hyperglycaemia and hyperinsulinemia much more in females than in males during an oral glucose tolerance test [36, 45]. In females with MetSy, increased circulating ucOC was detected with decreased TOC levels, but the same detection was not noted in their male counterparts [36, 49]. The responsibility for this gender difference has been attributed to testosterone. Studies have reported that increased ucOC levels promote testosterone production and secretion in male rodent models [36, 42, 50, 51]. Moreover, in clinical studies involving men with central obesity, TOC levels had a positive correlation with testosterone [36, 52]. The same applies to men with or without T2D [21, 36, 43]. In this study of individuals with obesity or overweight, women had higher levels of ucOC compared to men.
This study confirmed, as in other previous studies, the correlation of ucOC, which is supposed to be the active form of OC, with glucose metabolism, obesity markers, and insulin resistance and highlights that waist/hip ratio can be a predictor of ucOC.
In the last few years, a growing number of studies have elucidated the function of the bone as an active endocrine organ and, overall, the existing crosstalk between bone and insulin resistance. In addition to its effect as a possible insulin secretagogue, ucOC regulates overall metabolism and targets various organs and tissues, such as adipocytes, skeletal muscle, and the small intestine. Overall, these effects suggest that OC may play a role in protecting against insulin resistance and T2D.
Research into this area is ongoing, but it suggests that OC might be a target for developing new treatments for insulin resistance and T2D. However, more studies are needed to fully understand the mechanisms and potential therapeutic applications of OC in the treatment of insulin resistance.
This study confirmed that there is a correlation between the suggested active form of OC, ucOC, and insulin resistance as a companion occurrence of overweight and obesity in persons without any medical treatment affecting their OC levels and demonstrated that waist/hip ratio is a reliable measure to predict ucOC level in this population. However, the potential benefits of ucOC as a therapeutic agent for treating insulin resistance and MetSy in humans remain to be elucidated.
The study has not been published anywhere, but the data was presented as an abstract at the 30th European Congress of Obesity (2023), in Dublin, Ireland [32].
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Written By
Venera Berisha-Muharremi
Submitted: 15 May 2024Reviewed: 17 May 2024Published: 19 June 2024
Open access peer-reviewed chapter - ONLINE FIRST
