Obesity and diabetes are known metabolic diseases that result due to disturbance in the lipid and glucose metabolism leading to imbalance in energy homeostasis (1, 2). The prevalence of obesity has been continuously increasing in most countries since 1980, as per the report by the Global Burden of Disease Group in 2017 (3). Obesity is defined by a body mass index (BMI) of more than or equal to 30 kg/m2, which occurs due to the imbalance between energy intake and expenditure, resulting in excess accumulation of body fat (WHO and CDC). Another metabolic disease characterized by hyperglycemia and is increasing in prevalence is diabetes mellitus (DM), particularly T2DM, which accounts for 90–95% of all patients with diabetes and is expected to increase to 439 million by 2030 (4, 5). Both obesity and T2DM are complex metabolic disorders of multifaceted etiology accompanied by a series of complications, including macrovascular diseases (hypertension, hyperlipidemia, heart attacks, coronary artery disease, strokes, cerebral vascular disease, and peripheral vascular disease), microvascular diseases (retinopathy, nephropathy, and neuropathy), and cancers (6). Recently, studies have shown that bone health is also compromised in people with obesity and T2DM (7).

The skeletal system is highly dynamic and constantly undergoes repair and remodeling (8). Normal bone remodeling is necessary for fracture healing and skeleton adaptation to mechanical use. A disruption in the equilibrium between bone formation and resorption processes can result in bone-related diseases such as osteoporosis (9). Recently, bone has been recognized as an endocrine organ capable of synthesizing and secreting a variety of bioactive compounds that regulate bone remodeling and affect the metabolic processes throughout the body (9, 10). The endocrine function of bone is mediated through the secretion of several hormones, such as osteocalcin (OC), fibroblast growth factor 23 (FGF23), lipocalin 2 (Lcn2), and sclerostin (SOST) (11, 12).

SOST is a glycoprotein with a molecular weight of̴27 kDa, which is crucial in regulating bone metabolism (13). Encoded by the SOST gene, it is predominantly synthesized by osteocytes and is vital in maintaining bone homeostasis (14). SOST influences both bone formation and remodeling processes by acting as an inhibitory agent in the Wnt/β-catenin signaling pathway via binding to LDL receptor-related proteins 5/6 (LRP5/6) thereby negatively regulating bone formation (15, 16). Mutations in the SOST gene, leading to a deficiency of SOST, can give rise to two uncommon autosomal recessive bone-hardening conditions: Sclerosteosis and van Buchem disease (17).

Circulating SOST levels have been found to be altered in individuals with T2DM (18, 19). Patients with T2DM show higher circulating levels of SOST compared with healthy individuals. Since SOST is mainly produced by osteocytes this indicates that fluctuations in glucose levels could significantly impact the primary cells responsible for bone health. Specifically, when blood glucose levels vary considerably from the standard 80–140 mg/dL range it may negatively affect osteocytes (20). This is inferred from the observation that T2DM patients often display disrupted bone metabolism, making them more susceptible to fractures and other bone-related issues (12, 21). Notably, the risk of fractures in T2DM patients is nearly double that of healthy individuals, even if their bone mineral density (BMD) is normal or elevated (11). This points to potential issues with bone quality, possibly affecting its strength or micro-architecture. Moreover, Daniele et al. reported an increase in blood SOST levels, which was significantly associated with insulin resistance in skeletal muscle, liver, and adipose tissue in patients with diabetes (22). Additionally, in a study done on Indian male individuals who have been diagnosed with T2DM, the authors observed a notable increase in the levels of circulating SOST when compared to the healthy male control group (23). This finding was consistent with the expression levels of SOST mRNA. Furthermore, in a study done on SOST knockout mice the author showed that these mice exhibit increased bone mass, decreased fat mass, and increased insulin sensitivity (24). The authors also demonstrated that treatment with anti-SOST antibodies decreased fat mass in wild-type mice and enhanced differentiation of adipocytes.

The role of SOST in obesity and diabetes is well documented. We hypothesize that Individuals with obesity and T2DM will have higher circulating levels of SOST compared to healthy individuals. Additionally, we predict that ethnic variations within the population residing in Kuwait may influence SOST plasma levels due to the high prevalence of obesity and T2DM. This study aims to investigate the circulating level of SOST in the population living in Kuwait. Also, since the Kuwaiti population is comprised of people from different ethnic backgrounds, the impact of ethnic variation in relationships between SOST and obesity/diabetes was explored. Furthermore, the objective of this study is to identify the factors that may be associated with SOST levels and their possible health implications.

This large cross-sectional study provides insight into the potential factors affecting circulating SOST levels in a multiethnic population. The data presented in the current study showed that diabetes status, HbA1c, age, gender, and ethnicity are the major factors associated with circulating SOST levels. This observation was further confirmed by quantile regression analysis where the associations were independent and remained significant even after adjusting for confounders. We also showed that obesity does not affect circulating SOST levels, as shown by the lack of correlation and the results of the quantile regression.

Patients with T2DM exhibited significantly higher SOST levels compared to their non-diabetic counterparts. Moreover, we observed strong correlations between SOST and HbA1c, FBG, and HOMA-IR, which are measures of long-term blood sugar control, blood sugar level, and insulin sensitivity, respectively. Among these variables, HbA1c showed the highest correlation with SOST, suggesting that SOST may reflect the chronic effects of hyperglycemia on bone health. Furthermore, the adjusted model highlighted the independent associations of SOST with diabetes and HbA1c. Our findings are in accord with previous reports (18, 19, 23, 28). In addition, Pacicca and colleagues conducted an in vitro study using the IDG-SW3 osteocyte-like cell line. When cultured under high glucose conditions, these cells exhibited a significant increase in SOST mRNA (by 100-fold) and SOST protein (by 5000-fold) compared to cells in control media. These findings indicate that glucose levels directly influence osteocyte function via SOST expression, shedding light on a potential mechanism by which high glucose/diabetes adversely affects bone quality. While the exact mechanism by which glucose homeostasis influences SOST levels is not fully understood, it is believed to involve the Wnt signaling pathway. A number of studies have demonstrated that activation of the Wnt signaling pathway enhances glucose metabolism (29, 30). Wnt7b has been shown to affect glucose uptake, GLUT expression, and Akt activation during osteoclastogenesis (31). Additionally, Wnt3a may boost mitochondrial oxygen consumption (32), elevate energy output by augmenting glutamine use in the TCA cycle (33), and activate the mTORC2 and protein kinase B (Akt) pathways, leading to the upregulation of essential glycolytic enzymes (34).

The age-associated increase of circulating levels of SOST in this study is in line with most previous investigations (35–37). Possibly, this is due to the natural aging process, which is known to affect bone turnover and remodeling (9, 38). SOST inhibits osteoblast activity, making it a potential biomarker for bone formation. The fact that the amount of SOST in our bodies increases as we age indicates that its increased production may reflect bone structure rather than size.

Moreover, there was a significant gender difference in median SOST levels, with males exhibiting higher levels compared to females. Gender disparities were observed across various factors, including diabetes status, insulin resistance (IR), body weight classifications, age brackets, and ethnicities (as illustrated in Figures 3 , 4 ). For example, a notable rise in SOST levels was evident among men compared to women within the diabetes cohort, a pattern consistent among non-diabetics, those with normal glucose tolerance, individuals with insulin resistance, and participants across different body weight categories (normal, overweight, obese), age groups, and ethnic backgrounds (Arab, South Asian, Southeast Asian). Our study findings underscore the significant role of gender in the variability of SOST levels. This observation aligns with previous studies that have reported gender-based differences in circulating SOST (36, 39, 40). Moreover, In a study conducted by MÖdder et al. involving 362 women and 318 men from a population-based cohort, it was observed that men consistently had higher serum SOST levels than women regardless of age (41). The exact reasons for this difference remain uncertain. However, one hypothesis the authors suggested was that the higher SOST levels in men could be attributed to their larger skeletal mass, which might produce and release more SOST into the bloodstream. In a second interventional study, the authors assessed the effect of estrogen on circulating SOST levels in both genders (37). They used two distinct direct intervention study methodologies (estrogen treatment and estrogen withdrawal) and found that estrogen treatment leads to a decrease in serum SOST levels, while estrogen withdrawal causes an increase in SOST levels. This evidence strongly suggests that estrogen has a regulatory effect on circulating SOST levels and, potentially, the production of SOST by osteocytes in the bone. Apparently, both hormonal and bone mass differences between genders might play a role in influencing circulating SOST levels. However, the exact mechanisms underlying these differences need further investigation.

The influence of ethnicity on SOST levels has not been comprehensively investigated. While several studies have examined the ethnic impact on SOST levels (23, 42, 43), there is still a need for a more detailed understanding. The study we present is one of the few that examines ethnic differences in the levels of circulating SOST. Our findings suggest distinct ethnic-specific variations in circulating SOST levels among Arabs, South Asians, and Southeast Asians. Notably, South Asian participants exhibited the most pronounced association, even when accounting for factors like age, gender, BMI, and diabetes status. This is in agreement with the observation of Janssen L. et al. who observed elevated plasma SOST levels in South Asians compared to white Caucasians (44). While their comparison was with an ethnic group different from the groups examined in our study, it underscores the unique metabolic challenges faced by the South Asian population (45, 46). Another study, focusing on 138 healthy pre-menopausal and post-menopausal women, included Chinese American and white Caucasian participants to identify ethnic variation in serum SOST levels (42). Their findings showed no significant ethnic-specific variations in SOST levels. However, they did note that post-menopausal women had higher SOST levels than pre-menopausal women across both racial categories. It is worth noting that the first important difference between our study and the other is that our study compared South Asians and Southeast Asians with Arabs rather than Caucasians; secondly, we included both genders, whereas their study included only women, and lastly, our larger sample size enhances the robustness of our results.

The relationship between obesity and circulating SOST levels is unclear in the literature. While some studies indicate a rise in serum SOST levels with obesity (35, 47, 48), others have not identified such a link (30, 43). In our study, we used three different anthropometric measurements to evaluate obesity, BMI, WC, and HC. We did not find any significant correlation between SOST and BMI or HC, but we found a weak correlation between SOST and WC. This suggests that obesity may not be a major determinant of SOST levels, and that other factors may have more influence. Our result is more reliable than previous studies, as we used a large sample size (n=2083) that increased the statistical power and reduced the sampling error.

Although our study controlled for age, gender, diabetes status, and BMI, we did not include assessments for Metabolic Associated Fatty Liver Disease (MAFLD). This omission limits our understanding of the full impact of metabolic comorbidities on SOST. Future research should consider incorporating a wider range of metabolic conditions, including MAFLD, to provide a more comprehensive view of how obesity and related disorders influence SOST levels. We also did not assess bone mineral density (BMD) in our study. We acknowledge the significance of BMD as a key marker of bone health, particularly in relation to sclerostin levels. Such data could enrich our research findings and implications. We hope to explore this in future work, including a comprehensive bone health assessment. We believe that our study’s findings lay the groundwork for such investigations.

In conclusion, the study confirms that circulating level of SOST is impacted by diabetes. The positive association between the level of SOST and various blood markers that are related to different metabolic complications implies that it plays a detrimental role in the individual’s wellbeing. As for the ethnicity, South Asian participants had the highest levels of SOST across the three groups and exhibited the most pronounced association, even when accounting for factors like age, gender, BMI, and diabetes status. This shows that the level of SOST may have a stronger impact on health conditions among people of specific ethnic background. This also sheds light on the importance of personalized medicine to address the development of medications taking into consideration the ethnic background.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The study protocol was approved by the Ethics Review Committee at Dasman Diabetes Institute under the reference RA2011-003, and done in accordance with the principles of the Declaration of Helsinki and good clinical practice guidelines. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

TA: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis. PC: Writing – review & editing, Methodology, Investigation, Data curation. IA-K: Writing – review & editing, Methodology, Investigation, Data curation. MA-F: Writing – review & editing, Writing – original draft, Supervision, Investigation, Formal analysis, Conceptualization. TT: Writing – review & editing, Methodology, Investigation, Formal analysis. AA: Writing – review & editing, Software, Methodology, Formal analysis. FS: Writing – review & editing, Methodology, Investigation, Formal analysis. HA: Writing – review & editing, Methodology, Investigation, Formal analysis. MA-G: Writing – review & editing, Methodology, Investigation, Formal analysis. JT: Writing – review & editing, Methodology, Investigation, Formal analysis. HK: Writing – review & editing, Methodology, Investigation, Formal analysis. FA-M: Writing – review & editing, Writing – original draft, Resources, Investigation, Formal analysis. JA: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.