Serum Sclerostin as a Marker of Microvascular and Macrovascular Complications among Children and Adolescents with Type 1 Diabetes Mellitus

Serum Sclerostin as a Marker of Microvascular and Macrovascular Complications among Children and Adolescents with Type 1 Diabetes Mellitus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Serum Sclerostin as a Marker of Microvascular and Macrovascular Complications among Children and Adolescents with Type 1 Diabetes Mellitus Dina Ebrahem Sallam, Yamsin Elhenawy, Sara Taha, Aya Abdullah, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5734283/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 May, 2025 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Chronically uncontrolled diabetes mellitus (DM) is linked to long-term micro and macrovascular adverse outcomes, through speeding up atherosclerosis and peripheral vascular diseases. Owing to the early cardiac and renal involvement, an early diagnostic biomarker is required. Sclerostin is a Wnt-signaling inhibitor, having a pathophysiological role in vasculopathy, and could be used as a vasculopathy marker, nevertheless, few data are available in pediatric patients with type 1 diabetes mellitus (T1DM). We aimed at assessing its serum level, and the relation to diabetic microvascular and macrovascular complications. Methods : a case control study on pediatric and adolescent patients with T1DM, and healthy controls. Patients were divided according to proteinuria into non-diabetic nephropathy (DN), and DN group. Patients’ clinicodemographic, and anthropometric measurements were obtained, with withdrawal of fasting serum lipid profile, kidney function test, and serum sclerostin. Carotid intimal media thickness (CIMT), a marker of subclinical atherosclerosis, was measured. Results: We included 75 comparable subjects, where median (IQR) serum sclerostin levels was significantly higher in DN, compared to non-DN, and controls [90.83 (82.32 – 115.1), vs 33.29 (28.37 – 38.53), vs 13.5 (10.32 – 15.72) ng/ml respectively, p< 0.001]. Similarly, median (IQR) CIMT was significantly higher in DN, than non-DN and controls [1.1 (0.8 – 1.3), vs 0.11 (0.1 – 0.2), vs 0.11 (0.1 – 0.2) mm, p 60.0 ng/ml and CIMT >0.3 mm were able to detect DN. Conclusions: Serum Sclerostin levels could serve as a potential biomarker for micro and macrovascular complications in pediatric patients with T1DM. CIMT DN Sclerostin T1DM Figures Figure 1 Figure 2 Figure 3 Background Diabetes mellitus (DM) is chronic metabolic disease, that is typified by either absence or inadequate insulin production. Chronically uncontrolled DM is linked to long-term micro and macrovascular adverse outcomes as cardiovascular diseases (CVDs) and diabetic nephropathy (DN) respectively, through speeding up the atherosclerosis [1]. Renal affection in patients with diabetes occur as structural, clinical, and biological changes, starting soon after diabetes onset, in the form of thickening of the glomerular basement membrane, mesangial expansion [2] till appearance of albuminuria, and decreased glomerular filtration rate (GFR) [3] , that if left untreated, ends up with chronic kidney disease (CKD). This highlights the early onset of diabetic kidney disease (DKD). CVDs is a well-recognized comorbidity in patients with T1DM, where cardiovascular remodeling occurs early after the diagnosis, where previous studies indicates that adolescents and young people with T1DM have subclinical cardiac dysfunction, central aortic stiffness, and accelerated atherosclerosis and peripheral vascular disease [4, 5] . The carotid intima-media-thickness (CIMT) measurement is a credible surrogate marker for cardiovascular risk, where it gives an accurate data of early detection of atherosclerotic alterations, and hence CVDs [6] . Owing to the early cardiac and renal involvement in patients with diabetes, and although the screening for microalbuminuria that occurs later in uncontrolled diabetes is the widely used in the clinical practice as the "gold standard" diagnostic for predicting and identifying DKD in pediatrics [7] , an early diagnostic biomarker of CVDs and DN are required, for the early detection, close monitoring, and implementation of proper treatment strategy. Sclerostin is a Wnt-signaling inhibitor, that have a proven negative regulatory effect on the bone development, in addition, having a pathophysiological role in vascular aging process, where it has proinflammatory effect, that contributes to intimal thickening, vascular smooth muscle cell (VSMC) migration and proliferation, endothelial dysfunction, and accelerates the vascular calcification [8] . Sclerostin levels rise with ageing and remain higher in some disorders such as DM and CKD and raise CVDs. As a result, sclerostin is emerging as a marker for both clinical and subclinical vascular diseases [8, 9] . Nevertheless, few data are available on the relationship between serum sclerostin and diabetic angiopathy in pediatric and adolescent patients with T1DM. Thus, the primary objective of the current study was to assess the serum sclerostin levels among children and adolescents with type 1 diabetes mellitus (T1DM), and the secondary objective was to study the relation with diabetic angiopathies; in the form of DN (microvascular complication) and atherosclerotic (macrovascular complication). Methodology This was a case control study that was conducted at Pediatrics and Adolescents Diabetes and Nephrology units, Children’s Hospital, Faculty of Medicine, Ain Shams University, Egypt. The study was conducted after approvement of the local research ethics committee at our hospital (ASU MS 658/2022), where informed ascent and consent were obtained from all participants and their caregiver respectively. Patients diagnosed with T1DM according to ISPAD guidelines [10] were divided according to albuminuria into group 1; 25 normoalbuminuric patients with diabetes (non-DN), and group 2; 25 patients with diabetic nephropathy (DN). They were compared to 25 healthy age and gender matched controls. Participants with liver dysfunction, renal impairment, and proteinuria due to other causes than diabetes, and other autoimmune diseases, were excluded from the study. All T1DM patients were on basal/bolus insulin regimen. Patients and controls were subjected to detailed history, emphasis on demographic data, duration of disease, in addition to anthropometric measures, and measuring estimated glomerular filtration rate (eGFR) using revised bedside Schwartz formula [11] , fasting lipid profile, the mean HbA1c % over the last year prior to the study, urinary albumin-to-creatinine ratio (UACR) in early morning spot urine sample, where normal level is below 30 mg/g [12]. Serum Sclerostin level was measured using ELISA technique (BT lab, Shanghai, China, cat. no E3068Hu), where standard curve range between 0.5-200 ng/ml, with sensitivity of 0.26 ng/ml [13]. Carotid intima media thickness (CIMT) as an early marker for atherosclerosis, was measured at the middle part of right common carotid artery, using carotid doppler ultrasound scanner, with a 7–10.0-MHz linear array transducer following a predetermined standardized scanning protocol, where images of the carotid artery walls were captured and measured the distance between the lumen-intima interface and the media-adventitia interface. Statistical Analysis The collected data was revised, coded, and tabulated using statistical package for Social Science (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Data were presented and suitable analysis was done according to the type of data obtained for each parameter, where Shapiro-Wilk test was done to test the normality of data distribution, and descriptive statistics were analyzed using mean and standard deviation for parametric data, median and range for non-parametric data. Analytical statistics were performed using student t test to assess the statistical significance of the difference of parametric variable between two study group means, Mann Whitney test (U test) to assess the statistical significance of the difference of a non-parametric variable between two study groups, while Kruskal-Wallis test was used to assess the statistical significance of the difference of a non-parametric variable between more than two study groups, and Chi-Square test was used to examine the relationship between two qualitative variables, in addition to the correlation analysis was tested to assess the strength of association between two quantitative variables. The ROC Curve (receiver operating characteristic) provided a useful way to evaluate the sensitivity and specificity for quantitative diagnostic measures that categorize cases into one of two groups. The optimum cut off point was defined as that which maximized the AUC value, where AUC is that a test with an area greater than 0.9 has high accuracy, while 0.7–0.9 indicates moderate accuracy, 0.5–0.7, low accuracy and 0.5 a chance result. Results Clinical and demographic data of our studied cohort is illustrated in table 1. The current study included 75 participants divided equally into 3 groups: group 1 (non-DN patients), and group 2 (DN), and health controls with mean ± SD age of 11.18 ±3.16, 12.08 ± 2.29, and 10.80 ± 4.23 years respectively, where there was no statistically significant difference between them regarding the age, gender, and anthropometric measure (p>0.05). There was a significant difference between patients of group 1 and group 2 as regards the disease duration, where the patients with DN had longer duration of diabetes [ median (IQR)= 8 (6 – 11), vs 4 (3 – 5) years respectively, p<0.001]. As anticipated, patients with DN had higher levels of UACR (64.33±13.45 vs 9.87±3.21, p<0.001) and they had significantly higher levels of HbA1c% (11.13 ± 1.91 vs 10 ± 1.27%, p= 0.018), meanwhile, fasting lipid profile and eGFR was comparable between the T1DM groups (table 2). Serum sclerostin level was significantly higher in in all our T1DM patients compared to healthy controls while the median serum sclerostin level was significantly higher among patients with DN [90.83 (82.32–115.1) vs 33.29 (28.37–38.53), p<0.001] (table 1 and figure 1). Albeit CIMT hadn’t changed significantly between control and non-DN groups (p=0.7), nevertheless, it was significantly higher in DN than non-DN patients and controls, which was evident by post-hoc analysis [control 0.11 (0.1 – 0.2) vs non-DN 0.11 (0.1 – 0.2) vs DN 1.1 (0.8 – 1.3) ng/mL), p<0.001] (table 1 and figure 2). Among participants with T1DM, serum sclerostin level positively correlated with the disease duration, HbA1c%, UACR, and CIMT (r= 0.678, 0.426, 0.798, 0.66 respectively, p<0005) (table 2). Also, in DN group, serum sclerostin level significantly positively correlated with the duration of diabetes, HbA1C, and UAER, and CIMT (r= 0.678, 0.426, 0.798, 0.66 respectively, p<0005) (table 3). The accuracy of serum sclerostin and CIMT in the detection of DN among patients with T1DM is described by ROC, where a cut off value of serum sclerostin above 60.01 ng/ml was detected with AUC 0.986, with a sensitivity of 88% and a specificity of 100%, while for CIMT, a cut-off value above 0.3 mm was detected with AUC 0.998, with a sensitivity of 96 % and a specificity of 100% ( figure 3 ). Discussion In our study, serum sclerostin level was significantly higher in patients with diabetes than control, especially in DN group, which indicates an association of serum sclerostin level with glucose metabolism. Mechanisms involved in development and progression of DN are still unclear, however, the oxidative stress and vascular changes are incriminated and linked directly to DN pathophysiology, also, it is known that sclerostin have an approved role in vascular pathology and increased oxidative stress, especially in diabetic patient [14] , and a possible role in the development of DN. Very few previous studies on serums sclerostin level in pediatric and adolescent patients with T1DM are available, nevertheless, with controversial results, where a Japanese study [15] found a significantly higher sclerostin in T1DM in comparison to controls, additionally a previous study [16] reported that sclerostin could play an important role in the regulation of glucose metabolism in children and adolescents, regardless of other fat and bone-derived factors, meanwhile a previous study [17] found no differences in serum sclerostin levels between T1DM children and adolescents and their healthy peers. In our study, serum sclerostin positively correlated with HbA1c% and glycemic control, where higher serum sclerostin was associated with bad glycemic control. Previous pediatric study [18] highlighted the association between elevated blood levels of sclerostin and impaired glycemic control in children with T1DM, as well as the impact of continuous subcutaneous insulin infusion (CSII) on improving glycemic control, meanwhile, a previous study [16] revealed a negative association between serum sclerostin levels and HbA1c, nevertheless, a Japanese pediatric study [15] found no significant correlation between serum sclerostin levels and HbA1c in patients with T1DM. We found that serum sclerostin level in all our T1DM patients correlated positively with disease duration, where longer disease duration was associated with higher serum sclerostin level, however a previous study [19] revealed a similar positive correlation of serum sclerostin to the duration of the disease, however, it was an adult study on patients with T2DM. We found that serum sclerostin level in all our T1DM patients didn’t correlate with the gender, where this result was in accordance with previous Japanese study [15] , however previous studies demonstrated an association with the gender in both children and adults with T1DM, where it was [20] found that serum sclerostin level was elevated in males than females with T1DM, meanwhile, a previous study [21] found that females with T1DM had an elevated levels than males. This observation was different in patients T2DM, where the sclerostin level did not changed significantly between males and females, which could be explained by the variations in insulin levels and method of action between the two forms of diabetes, and hence sclerostin function [22]. We used CIMT as a marker for subclinical atherosclerosis, where it was significantly elevated in patients with diabetes with DN, then non-DN patients, and controls, which was confirmed by post-hoc analysis. This confirms that patients with DN have a risk of development of atherosclerosis and hence macrovascular complications, owing to many mechanisms including endothelial dysfunction, and glycocalyx disruption, which explain why patients with diabetes with albuminuria have a notably greater cardiovascular event risk than diabetics with normoalbuminuria [23, 24] . Additionally in our study we found that CIMT correlated positively with serum sclerostin level in all our T1DM patients, also this relation was highlighted in DN group who are at high risk of diabetic macroangiopathy. Our result is supported with the previous studies [25, 26] , where they had shown that sclerostin was expressed and detected in the VSMCs of atherosclerotic plaques, and in the aorta of patients undergoing aortic valve replacement and is elevated in VSMCs and calcified valvular plaques, pointing to its role in atherosclerosis development. The cutoff level of serum sclerostin and CIMT in detection of DN among pediatric and adolescent patients with T1DM was measured and described by ROC curve, where a serum sclerostin cut off value above 60.01 ng/mL, with AUC of 0.986, with a sensitivity of 88% and a specificity of 100%, in addition to CIMT cut-off value above 0.3 mm with AUC of 0.998, with a sensitivity of 96 % and a specificity of 100% could diagnose DN accurately, and would be used as a novel biomarker of DN before deterioration of renal function. Up to our knowledge, no previous publication that studied the cut off level of serum sclerostin and CIMT to detect diagnose DN, hence we recommend further studies on wider scale to study the sensitivity of these markers as early detectors of DN. Our study is one of its kind owing to measuring the serum sclerostin level in Egyptian homogenous cohort of pediatric and adolescent patients with T1DM with and without DN, in comparison to healthy controls. Additionally, this work presents new information that may point to sclerostin's involvement in T1DM micro- and macrovascular complications. The limitation of our study was the relatively small sample sizes and being a single center. Conclusion Serum sclerostin level was statistically significantly higher in DN, and correlated positively with the disease duration, poor glycemic control, and albuminuria level. CIMT as a marker of atherosclerosis and hence macrovascular complication, was significantly higher in DN, and associated with higher serum sclerostin levels. The findings from current study support the increasing understanding that elevated serum sclerostin levels may be related to diabetic angiopathy, and it is imperative that subsequent studies assess the viability of sclerostin as a biomarker for identifying patients at risk for vascular complications and explore whether further investigation into this pathway could lead to the development of novel therapeutic targets. 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All subjects Controls n = 25 Group 1 (DM, non-DN) n = 25 Group 2 (DN) n = 25 p-value Age (years) Mean ± SD 10.80 ± 4.23 11.18 ± 3.16 12.08 ± 2.29 0.381 Range 7-14 7– 15 7-17 Gender (n, %) Female 13 (52.0%) 16 (64.0%) 18 (72.0%) 0.339 Male 12 (48.0%) 9 (36.0%) 7 (28.0%) BMI SDS Median (IQR) 0.55 (0.4-1) 0.48(0.11-1) 0.53(0.3-0.9) 0.305 Duration of diabetes (years) Median (IQR) 4 (3 – 5) 8 (6 – 11) 0.000 Serum creatinine (mg/dL) Mean ± SD 0.37 ± 0.12 0.41 ± 0.15 0.39 ± 0.19 0.73 Range 0.1 – 0.6 0.2 – 0.7 0.2 – 0.7 eGFR (ml/min/1.73m 2 ) Mean ± SD 108.31±6.82 109.7±5.32 0.4223 HbA1c % Mean ± SD 10 ± 1.27 11.13 ± 1.91 0.018 Total serum cholesterol (mg/dL) Median (IQR) 100 (50 – 149) 86 (60 – 160) 0.946 Serum Triglycerides (mg/dL) Median (IQR) 82 (65 – 113) 110 (66 – 124) 0.228 UACR (mg/g creatinine) Mean ± SD 9.87±3.21 64.33±13.45 <0.001 Serum Sclerostin (ng/ml) Median (IQR) 13.5 (10.32 – 15.72) 33.29 (28.37 – 38.53) 90.83 (82.32 – 115.1) Range 7.03 – 19.33 17.23 – 60.01 43.63 – 145.8 CIMT (mm) Median (IQR) 0.11 (0.1 – 0.2) 0.11 (0.1 – 0.2) 1.1 (0.8 – 1.3) Range 0.1 – 0.3 0.01 – 0.3 0.3 – 2 BMI: body mass index; CIMT: carotid intima media thickness, DM: diabetes mellitus, DN: diabetic nephropathy, eGFR: estimated glomerular filtration ratio, HBA1c: hemoglobin A1c, SD: standard deviation, UACR: urinary albumin creatinine ratio Table (2): Correlation of serum Sclerostin and CIMT with other studied parameters among all participants with T1DM. All T1DM patients (n = 50) Serum Sclerostin CIMT r p-value r p-value Age (years) 0.132 0.371 0.034 0.784 Disease duration (years) 0.678** 0.000 0.617** 0.000 HbA1c% 0.426** 0.002 0.436** 0.002 Microalbuminuria (mg/gm) 0.798** 0.000 0.798** 0.000 Cholesterol (mg/dL) 0.022 0.881 -0.022 0.878 Triglycerides (mg/dL) 0.155 0.284 0.114 0.432 Serum Sclerostin (ng/mL) - - 0.66 <0.001 CIMT (mm) 0.66 <0.001 - - CIMT: carotid intima media thickness, DM: diabetes mellitus, HBA1c%: Hemoglobin A1c%, r: Spear-man correlation coefficient. Table (3): Correlation of serum Sclerostin and CIMT with other studied parameters among participants with DN. DN group Sclerostin factor CIMT r P-value r P-value Age (years) 0.176 0.400 0.174 0.405 Duration(years) 0.507** 0.004 0.469** 0.005 HbA1c % 0.688** 0.000 0.753** 0.000 Microalbuminuria 0.798** 0.000 0.617** 0.001 Cholesterol(mg/dL) 0.089 0.672 0.154 0.461 Triglycerides (mg/dL) 0.060 0.775 0.055 0.796 CIMT (mm) 0.512 0.009 Serum Sclerostin level (ng/mL) 0.512 0.009 CIMT, carotid intima media thickness; DN, diabetic nephropathy; HBA1c, hemoglobin A1c; TG, triglyceride. P-value > 0.05: Non-significant; P-value < 0.05: Significant; P-value < 0.01: Highly significant; r, Spearman correlation coefficient. Cite Share Download PDF Status: Published Journal Publication published 12 May, 2025 Read the published version in Pediatric Nephrology → Version 1 posted Editorial decision: Major Revisions Needed 30 Jan, 2025 Reviewers agreed at journal 30 Dec, 2024 Reviewers invited by journal 30 Dec, 2024 Editor assigned by journal 30 Dec, 2024 First submitted to journal 29 Dec, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5734283","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":395954925,"identity":"282b1b41-eb47-4e60-a064-dd87f3b73c7d","order_by":0,"name":"Dina Ebrahem Sallam","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-4684-229X","institution":"Ain Shams University Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Dina","middleName":"Ebrahem","lastName":"Sallam","suffix":""},{"id":395954926,"identity":"d2dd2de0-1c88-4d28-be10-48dd72b63959","order_by":1,"name":"Yamsin Elhenawy","email":"","orcid":"","institution":"Ain Shams University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yamsin","middleName":"","lastName":"Elhenawy","suffix":""},{"id":395954927,"identity":"4ea02841-a06e-4274-b711-757cc110eb57","order_by":2,"name":"Sara Taha","email":"","orcid":"","institution":"Ain Shams University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Taha","suffix":""},{"id":395954928,"identity":"ab81e73e-7e01-4e95-b3f7-e036f9492070","order_by":3,"name":"Aya Abdullah","email":"","orcid":"","institution":"Ain Shams University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Aya","middleName":"","lastName":"Abdullah","suffix":""},{"id":395954929,"identity":"35ad6427-867f-4f44-84f2-07a7c287d1c4","order_by":4,"name":"Iman Elsayed","email":"","orcid":"","institution":"Ain Shams University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Iman","middleName":"","lastName":"Elsayed","suffix":""}],"badges":[],"createdAt":"2024-12-30 09:19:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5734283/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5734283/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-025-06793-3","type":"published","date":"2025-05-12T15:57:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72841092,"identity":"49c4992d-8698-44ce-900b-c1f642ad74a9","added_by":"auto","created_at":"2025-01-02 18:19:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70468,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCIMT (mm) among the studied cohort.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5734283/v1/1225b794da47abe51dcfabcf.png"},{"id":72842065,"identity":"5e616a87-3ace-4c6f-9c64-7cdf1de32013","added_by":"auto","created_at":"2025-01-02 18:27:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":83057,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum Sclerostin levels (ng/mL) among the studied cohort\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5734283/v1/5128b279baf88975a4e1c91c.png"},{"id":72841091,"identity":"e542c3ef-ee1e-4c77-b962-5a4017135bd8","added_by":"auto","created_at":"2025-01-02 18:19:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":135310,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve of serum Sclerostin and CIMT in DN.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5734283/v1/1a416f9d239a3f276ff1cd1e.png"},{"id":83067817,"identity":"19975e0f-e050-46b0-90fc-b98cf55d3fe2","added_by":"auto","created_at":"2025-05-19 16:06:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1601669,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5734283/v1/c31c2d12-b059-49d3-b789-ebbc73f2f715.pdf"}],"financialInterests":"","formattedTitle":"Serum Sclerostin as a Marker of Microvascular and Macrovascular Complications among Children and Adolescents with Type 1 Diabetes Mellitus","fulltext":[{"header":"Background","content":"\u003cp\u003eDiabetes mellitus (DM) is chronic metabolic disease, that is typified by either absence or inadequate insulin production. Chronically uncontrolled DM is linked to long-term micro and macrovascular adverse outcomes as cardiovascular diseases (CVDs) and diabetic nephropathy (DN) respectively, through speeding up the atherosclerosis\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e[1].\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eRenal\u0026nbsp;affection\u0026nbsp;in patients with diabetes occur as\u0026nbsp;structural,\u0026nbsp;clinical, and biological\u0026nbsp;changes, starting soon after diabetes onset, in the form of\u0026nbsp;thickening of the glomerular basement membrane, mesangial expansion\u0026nbsp;\u003cstrong\u003e[2]\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003etill appearance of albuminuria, and decreased glomerular filtration rate (GFR) \u003cstrong\u003e[3]\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e,\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ethat if left untreated, ends up with chronic kidney disease (CKD). This highlights the early onset of diabetic kidney disease (DKD).\u003c/p\u003e\n\u003cp\u003eCVDs is a well-recognized comorbidity in patients with T1DM, where cardiovascular remodeling occurs early after the diagnosis, where previous studies indicates that adolescents and young people with T1DM have subclinical cardiac dysfunction, central aortic stiffness, and accelerated atherosclerosis and peripheral vascular disease \u003cstrong\u003e[4, 5]\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThe carotid intima-media-thickness (CIMT) measurement is a credible surrogate marker for cardiovascular risk, where it gives an accurate data of early detection of atherosclerotic alterations, and hence CVDs \u003cstrong\u003e[6]\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOwing to the early cardiac and renal involvement in patients with diabetes, and although the screening for microalbuminuria that occurs later in uncontrolled diabetes is the widely used in the clinical practice as the \u0026quot;gold standard\u0026quot; diagnostic for predicting and identifying DKD in pediatrics \u003cstrong\u003e[7]\u003cem\u003e,\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ean early diagnostic biomarker of CVDs and DN are required, for the early detection, close monitoring, and implementation of proper treatment strategy.\u003c/p\u003e\n\u003cp\u003eSclerostin is a Wnt-signaling inhibitor, that have a proven negative regulatory effect on the bone development, in addition, having a pathophysiological role in vascular aging process, where it has proinflammatory effect, that contributes to intimal thickening, vascular smooth muscle cell (VSMC) migration and proliferation, endothelial dysfunction, and accelerates the vascular calcification \u003cstrong\u003e[8]\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eSclerostin levels rise with ageing and remain higher in some disorders such as DM and CKD and raise CVDs. As a result, sclerostin is emerging as a marker for both clinical and subclinical vascular diseases \u003cstrong\u003e[8, 9]\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eNevertheless, few data are available on the relationship between serum sclerostin and diabetic angiopathy in pediatric and adolescent patients with T1DM.\u003c/p\u003e\n\u003cp\u003eThus, the primary objective of the current study was to assess the serum sclerostin levels among children and adolescents with type 1 diabetes mellitus (T1DM), and the secondary objective was to study the relation with diabetic angiopathies; in the form of DN (microvascular complication) and atherosclerotic (macrovascular complication).\u003c/p\u003e\n"},{"header":"Methodology","content":"\u003cp\u003eThis was a case control study that was conducted at Pediatrics and Adolescents Diabetes and Nephrology units, Children\u0026rsquo;s Hospital, Faculty of Medicine, Ain Shams University, Egypt. The study was conducted after approvement of the local research ethics committee at our hospital (ASU MS 658/2022), where informed ascent and consent were obtained from all participants and their caregiver respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients diagnosed with T1DM according to ISPAD guidelines \u003cstrong\u003e[10]\u003c/strong\u003e were divided according to albuminuria into group 1; 25 normoalbuminuric patients with diabetes (non-DN), and group 2; 25 patients with diabetic nephropathy (DN). They were compared to 25 healthy age and gender matched controls. Participants with liver dysfunction, renal impairment, and proteinuria due to other causes than diabetes, and other autoimmune diseases, were excluded from the study. All T1DM patients were on basal/bolus insulin regimen. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients and controls were subjected to detailed history, emphasis on demographic data, duration of disease, in addition to anthropometric measures, and measuring estimated glomerular filtration rate (eGFR) using revised bedside Schwartz formula \u003cstrong\u003e[11]\u003c/strong\u003e, fasting lipid profile, the mean HbA1c % over the last year prior to the study, urinary albumin-to-creatinine ratio (UACR) in early morning spot urine sample, where normal level is below 30 mg/g \u003cstrong\u003e[12].\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum Sclerostin level\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ewas measured using ELISA technique (BT lab, Shanghai, China, cat. no E3068Hu), where standard curve range between 0.5-200 ng/ml, with sensitivity of 0.26 ng/ml \u003cstrong\u003e[13].\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCarotid intima media thickness (CIMT) as an early marker for atherosclerosis, was measured at the middle part of right common carotid artery, using carotid doppler ultrasound scanner, with a 7\u0026ndash;10.0-MHz linear array transducer following a predetermined standardized scanning protocol, where images of the carotid artery walls were captured and measured the distance between the lumen-intima interface and the media-adventitia interface.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe collected data was revised, coded, and tabulated using statistical package for Social Science (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Data were presented and suitable analysis was done according to the type of data obtained for each parameter, where Shapiro-Wilk test was done to test the normality of data distribution, and descriptive statistics were analyzed using mean and standard deviation for parametric data, median and range for non-parametric data. Analytical statistics were performed using student t test to assess the statistical significance of the difference of parametric variable between two study group means, Mann Whitney test (U test) to assess the statistical significance of the difference of a non-parametric variable between two study groups, while Kruskal-Wallis test was used to assess the statistical significance of the difference of a non-parametric variable between more than two study groups, and Chi-Square test was used to examine the relationship between two qualitative variables, in addition to the correlation analysis was tested to assess the strength of association between two quantitative variables. The ROC Curve (receiver operating characteristic) provided a useful way to evaluate the sensitivity and specificity for quantitative diagnostic measures that categorize cases into one of two groups. The optimum cut off point was defined as that which maximized the AUC value, where AUC is that a test with an area greater than 0.9 has high accuracy, while 0.7\u0026ndash;0.9 indicates moderate accuracy, 0.5\u0026ndash;0.7, low accuracy and 0.5 a chance result.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eClinical and demographic data of our studied cohort is illustrated in \u003cstrong\u003e\u003cem\u003etable 1.\u003c/em\u003e\u003c/strong\u003e The current study included 75 participants divided equally into 3 groups: group 1 (non-DN patients), and group 2 (DN), and health controls with mean \u0026plusmn; SD age of 11.18 \u0026plusmn;3.16, 12.08 \u0026plusmn; 2.29, and 10.80 \u0026plusmn; 4.23 years respectively, where there was no statistically significant difference between them regarding the age, gender, and anthropometric measure (p\u0026gt;0.05). There was a significant difference between patients of group 1 and group 2 as regards the disease duration, where the patients with DN had longer duration of diabetes [ median (IQR)= 8 (6 \u0026ndash; 11), vs 4 (3 \u0026ndash; 5) years respectively, p\u0026lt;0.001]. As anticipated, patients with DN had higher levels of UACR (64.33\u0026plusmn;13.45 vs 9.87\u0026plusmn;3.21, p\u0026lt;0.001) and they had significantly higher levels of HbA1c% (11.13 \u0026plusmn; 1.91 vs 10 \u0026plusmn; 1.27%, p= 0.018), meanwhile, fasting lipid profile and eGFR was comparable between the T1DM groups \u003cstrong\u003e\u003cem\u003e(table 2).\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum sclerostin level was significantly higher in in all our T1DM patients compared to healthy controls while the median serum sclerostin level was significantly higher among patients with DN [90.83 (82.32\u0026ndash;115.1) vs 33.29 (28.37\u0026ndash;38.53), p\u0026lt;0.001] (table 1 and figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eAlbeit CIMT hadn\u0026rsquo;t changed significantly between control and non-DN groups (p=0.7), nevertheless, it was significantly higher in DN than non-DN patients and controls, which was evident by post-hoc analysis [control 0.11 (0.1 \u0026ndash; 0.2) vs non-DN 0.11 (0.1 \u0026ndash; 0.2) vs DN 1.1 (0.8 \u0026ndash; 1.3) ng/mL), p\u0026lt;0.001] (table 1 and figure 2).\u003c/p\u003e\n\u003cp\u003eAmong participants with T1DM, serum sclerostin level positively correlated with the disease duration, HbA1c%, UACR, and CIMT \u003cstrong\u003e\u003cem\u003e(r= 0.678, 0.426, 0.798, 0.66 respectively, p\u0026lt;0005) (table 2). Also,\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ein DN group, serum sclerostin level significantly positively correlated with the duration of diabetes, HbA1C, and UAER, and CIMT \u003cstrong\u003e\u003cem\u003e(r= 0.678, 0.426, 0.798, 0.66 respectively, p\u0026lt;0005) (table 3).\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThe accuracy of serum sclerostin and CIMT in the detection of DN among patients with T1DM is described by ROC, where a cut off value of serum sclerostin above 60.01 ng/ml was detected with AUC 0.986, with a sensitivity of 88% and a specificity of 100%, while for CIMT, a cut-off value above 0.3 mm was detected with AUC 0.998, with a sensitivity of 96 % and a specificity of 100% (\u003cstrong\u003e\u003cem\u003efigure 3\u003c/em\u003e\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, serum sclerostin level was significantly higher in patients with diabetes than control, especially in DN group, which indicates an association of serum sclerostin level with glucose metabolism.\u0026nbsp;Mechanisms involved in development and progression of DN are still unclear, however, the oxidative stress and vascular changes are incriminated and linked directly to DN pathophysiology, also, it is known that sclerostin have an approved role in vascular pathology and increased oxidative stress, especially in diabetic patient \u003cstrong\u003e[14]\u003c/strong\u003e, and a possible role in the development of DN.\u003c/p\u003e\n\u003cp\u003eVery few previous studies on serums sclerostin level in pediatric and adolescent patients with T1DM are available, nevertheless, with controversial results, where a Japanese study\u0026nbsp;\u003cstrong\u003e[15]\u003c/strong\u003e found a significantly higher sclerostin in T1DM in comparison to controls, additionally a previous study \u003cstrong\u003e[16]\u003c/strong\u003e reported that sclerostin could play an important role in the regulation of glucose metabolism in children and adolescents, regardless of other fat and bone-derived factors, meanwhile a previous study \u003cstrong\u003e[17]\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003efound no differences in serum sclerostin levels between T1DM children and adolescents and their healthy peers.\u003c/p\u003e\n\u003cp\u003eIn our study, serum sclerostin positively correlated with HbA1c% and glycemic control, where higher serum sclerostin was associated with bad glycemic control. Previous pediatric study\u0026nbsp;\u003cstrong\u003e[18]\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ehighlighted the association between elevated blood levels of sclerostin and impaired glycemic control in children with T1DM, as well as the impact of continuous subcutaneous insulin infusion (CSII) on improving glycemic control, meanwhile, a previous study \u003cstrong\u003e[16]\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003erevealed a negative association between serum sclerostin levels and HbA1c, nevertheless, a Japanese pediatric study\u0026nbsp;\u003cstrong\u003e[15]\u003c/strong\u003e found no significant correlation between serum sclerostin levels and HbA1c in patients with T1DM. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe found that serum sclerostin level in all our T1DM patients correlated positively with disease duration, where longer disease duration was associated with higher serum sclerostin level, however a previous study\u0026nbsp;\u003cstrong\u003e[19]\u003c/strong\u003e revealed a similar positive correlation of serum sclerostin to the duration of the disease, however, it was an adult study on patients with T2DM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe found that serum sclerostin level in all our T1DM patients didn\u0026rsquo;t correlate with the gender, where this result was in accordance with previous Japanese study\u0026nbsp;\u003cstrong\u003e[15]\u003c/strong\u003e, however previous studies demonstrated an association with the gender in both children and adults with T1DM, where it was\u0026nbsp;\u003cstrong\u003e[20]\u003c/strong\u003e found that serum sclerostin level was elevated in males than females with T1DM, meanwhile, a previous study \u0026nbsp;\u003cstrong\u003e[21]\u003c/strong\u003e\u0026nbsp; found that females with T1DM had an elevated levels than males. This observation was different in patients T2DM, where the sclerostin level did not changed significantly between males and females, which could be explained by the variations in insulin levels and method of action between the two forms of diabetes, and hence sclerostin function\u0026nbsp;\u003cstrong\u003e[22].\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe used CIMT as a marker for subclinical atherosclerosis, where it was significantly elevated in patients with diabetes with DN, then non-DN patients, and controls, which was confirmed by post-hoc analysis. This confirms that patients with DN have a risk of development of atherosclerosis and hence macrovascular complications, owing to many mechanisms including endothelial dysfunction, and glycocalyx disruption, which explain why patients with diabetes with albuminuria have a notably greater cardiovascular event risk than diabetics with normoalbuminuria\u0026nbsp;\u003cstrong\u003e[23, 24]\u003cem\u003e.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eAdditionally in our study we found that CIMT correlated positively with serum sclerostin level in all our T1DM patients, also this relation was highlighted in DN group who are at high risk of diabetic macroangiopathy. Our result is supported with the previous studies\u0026nbsp;\u003cstrong\u003e[25, 26]\u003cem\u003e,\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ewhere they had shown that sclerostin was expressed and detected in the VSMCs of atherosclerotic plaques, and in the aorta of patients undergoing aortic valve replacement and is elevated in VSMCs and calcified valvular plaques, pointing to its role in atherosclerosis development.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe cutoff level of serum sclerostin and CIMT in detection of DN among pediatric and adolescent patients with T1DM was measured and described by ROC curve, where a serum sclerostin cut off value above 60.01 ng/mL, with AUC of 0.986, with a sensitivity of 88% and a specificity of 100%, in addition to CIMT cut-off value above 0.3 mm with AUC of 0.998, with a sensitivity of 96 % and a specificity of 100% could diagnose DN accurately, and would be used as a novel biomarker of DN before deterioration of renal function. Up to our knowledge, no previous publication that studied the cut off level of serum sclerostin and CIMT to detect diagnose DN, hence we recommend further studies on wider scale to study the sensitivity of these markers as early detectors of DN.\u003c/p\u003e\n\u003cp\u003eOur study is one of its kind owing to measuring the serum sclerostin level in Egyptian homogenous cohort of pediatric and adolescent patients with T1DM with and without DN, in comparison to healthy controls. Additionally, this work presents new information that may point to sclerostin\u0026apos;s involvement in T1DM micro- and macrovascular complications. The limitation of our study was the relatively small sample sizes and being a single center.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSerum sclerostin level was statistically significantly higher in DN, and correlated positively with the disease duration, poor glycemic control, and albuminuria level. CIMT as a marker of atherosclerosis and hence macrovascular complication, was significantly higher in DN, and associated with higher serum sclerostin levels. The findings from current study support the increasing understanding that elevated serum sclerostin levels may be related to diabetic angiopathy, and it is imperative that subsequent studies assess the viability of sclerostin as a biomarker for identifying patients at risk for vascular complications and explore whether further investigation into this pathway could lead to the development of novel therapeutic targets.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003eNon applicable\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests and Funding:\u003c/strong\u003e Non applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe would like to acknowledge our patients and their caregivers who joined this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSagoo, M. K., \u0026amp; Gnudi, L. (2020). Diabetic Nephropathy: An Overview. Methods in molecular biology (Clifton, N.J.), 2067, 3\u0026ndash;7. https://doi.org/10.1007/978-1-4939-9841-8_1\u003c/li\u003e\n\u003cli\u003eMarshall C. B. (2016). Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?. American journal of physiology. Renal physiology, 311(5), F831\u0026ndash;F843. https://doi.org/10.1152/ajprenal.00313.2016\u003c/li\u003e\n\u003cli\u003eAfkarian M. (2015). Diabetic kidney disease in children and adolescents. Pediatric nephrology (Berlin, Germany), 30(1), 65\u0026ndash;71. https://doi.org/10.1007/s00467-014-2796-5\u003c/li\u003e\n\u003cli\u003eBjornstad, P., Donaghue, K. C., \u0026amp; Maahs, D. M. (2018). Macrovascular disease and risk factors in youth with type 1 diabetes: time to be more attentive to treatment?. The lancet. Diabetes \u0026amp; endocrinology, 6(10), 809\u0026ndash;820. https://doi.org/10.1016/S2213-8587(18)30035-4\u003c/li\u003e\n\u003cli\u003eMarcovecchio, M. L., Dalton, R. N., Daneman, D., Deanfield, J., Jones, T. W., Neil, H. A. W., Dunger, D. B., \u0026amp; Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT) study group (2019). A new strategy for vascular complications in young people with type 1 diabetes mellitus. Nature reviews. Endocrinology, 15(7), 429\u0026ndash;435. https://doi.org/10.1038/s41574-019-0198-2\u003c/li\u003e\n\u003cli\u003eDalla Pozza, R., Ehringer-Schetitska, D., Fritsch, P., Jokinen, E., Petropoulos, A., Oberhoffer, R., \u0026amp; Association for European Paediatric Cardiology Working Group Cardiovascular Prevention (2015). Intima media thickness measurement in children: A statement from the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention endorsed by the Association for European Paediatric Cardiology. Atherosclerosis, 238(2), 380\u0026ndash;387. https://doi.org/10.1016/j.atherosclerosis.2014.12.029\u003c/li\u003e\n\u003cli\u003eSalem, N. A., El Helaly, R. M., Ali, I. M., Ebrahim, H. A. A., Alayooti, M. M., El Domiaty, H. A., \u0026amp; Aboelenin, H. M. (2020). Urinary Cyclophilin A and serum Cystatin C as biomarkers for diabetic nephropathy in children with type 1 diabetes. Pediatric diabetes, 21(5), 846\u0026ndash;855. https://doi.org/10.1111/pedi.13019\u003c/li\u003e\n\u003cli\u003eCatalano, A., Bellone, F., Morabito, N., \u0026amp; Corica, F. (2020). Sclerostin and Vascular Pathophysiology. International journal of molecular sciences, 21(13), 4779. https://doi.org/10.3390/ijms21134779\u003c/li\u003e\n\u003cli\u003eShalash, M. A. M., Rohoma, K. H., Kandil, N. S., Abdel Mohsen, M. A., \u0026amp; Taha, A. A. F. (2019). Serum sclerostin level and its relation to subclinical atherosclerosis in subjects with type 2 diabetes. Journal of diabetes and its complications, 33(8), 592\u0026ndash;597. https://doi.org/10.1016/j.jdiacomp.2019.04.012\u003c/li\u003e\n\u003cli\u003eLibman, I., Haynes, A., Lyons, S., Pradeep, P., Rwagasor, E., Tung, J. Y., Jefferies, C. A., Oram, R. A., Dabelea, D., \u0026amp; Craig, M. E. (2022). ISPAD Clinical Practice Consensus Guidelines 2022: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatric diabetes, 23(8), 1160\u0026ndash;1174. https://doi.org/10.1111/pedi.13454\u003c/li\u003e\n\u003cli\u003eSchwartz, G. J., Mu\u0026ntilde;oz, A., Schneider, M. F., Mak, R. H., Kaskel, F., Warady, B. A., \u0026amp; Furth, S. L. (2009). New equations to estimate GFR in children with CKD. Journal of the American Society of Nephrology : JASN, 20(3), 629\u0026ndash;637. https://doi.org/10.1681/ASN.2008030287\u003c/li\u003e\n\u003cli\u003eMattix, H. J., Hsu, C. Y., Shaykevich, S., \u0026amp; Curhan, G. (2002). Use of the albumin/creatinine ratio to detect microalbuminuria: implications of sex and race. Journal of the American Society of Nephrology : JASN, 13(4), 1034\u0026ndash;1039. https://doi.org/10.1681/ASN.V1341034\u003c/li\u003e\n\u003cli\u003eMcNulty M, Singh RJ, Li X, Bergstralh EJ, Kumar R. Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays. J Clin Endocrinol Metab. 2011 Jul;96(7):E1159-62. doi: 10.1210/jc.2011-0254\u003c/li\u003e\n\u003cli\u003eSabancilar, I., Unsal, V., Demir, F., Toprak, G., \u0026amp; Pekkolay, Z. (2023). Does oxidative status affect serum sclerostin levels in patients with type 2 diabetes mellitus?. Folia medica, 65(1), 46\u0026ndash;52. https://doi.org/10.3897/folmed.65.e72953\u003c/li\u003e\n\u003cli\u003eIshikawa, S., Takahashi, I., \u0026amp; Takahashi, T. (2023). SERUM SCLEROSTIN LEVELS IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS. 秋田医学, 50(2), 39-48.\u003c/li\u003e\n\u003cli\u003eWędrychowicz, A., Sztefko, K., \u0026amp; Starzyk, J. B. (2019). Sclerostin and its association with insulin resistance in children and adolescents. Bone, 120, 232\u0026ndash;238. https://doi.org/10.1016/j.bone.2018.07.021\u003c/li\u003e\n\u003cli\u003eTsentidis, C., Gourgiotis, D., Kossiva, L., Marmarinos, A., Doulgeraki, A., \u0026amp; Karavanaki, K. (2017). Increased levels of Dickkopf-1 are indicative of Wnt/\u0026beta;-catenin downregulation and lower osteoblast signaling in children and adolescents with type 1 diabetes mellitus, contributing to lower bone mineral density. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 28(3), 945\u0026ndash;953. https://doi.org/10.1007/s00198-016-3802-5\u003c/li\u003e\n\u003cli\u003eFaienza, M. F., Ventura, A., Delvecchio, M., Fusillo, A., Piacente, L., Aceto, G., Colaianni, G., Colucci, S., Cavallo, L., Grano, M., \u0026amp; Brunetti, G. (2017). High Sclerostin and Dickkopf-1 (DKK-1) Serum Levels in Children and Adolescents With Type 1 Diabetes Mellitus. The Journal of clinical endocrinology and metabolism, 102(4), 1174\u0026ndash;1181. https://doi.org/10.1210/jc.2016-2371\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a-Mart\u0026iacute;n, A., Rozas-Moreno, P., Reyes-Garc\u0026iacute;a, R., Morales-Santana, S., Garc\u0026iacute;a-Fontana, B., Garc\u0026iacute;a-Salcedo, J. A., \u0026amp; Mu\u0026ntilde;oz-Torres, M. (2012). Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. The Journal of clinical endocrinology and metabolism, 97(1), 234\u0026ndash;241. https://doi.org/10.1210/jc.2011-2186\u003c/li\u003e\n\u003cli\u003eM\u0026ouml;dder, U. I., Hoey, K. A., Amin, S., McCready, L. K., Achenbach, S. J., Riggs, B. L., Melton, L. J., 3rd, \u0026amp; Khosla, S. (2011). Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 26(2), 373\u0026ndash;379. https://doi.org/10.1002/jbmr.217\u003c/li\u003e\n\u003cli\u003eCatalano, A., Pintaudi, B., Morabito, N., Di Vieste, G., Giunta, L., Bruno, M. L., Cucinotta, D., Lasco, A., \u0026amp; Di Benedetto, A. (2014). Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus. European journal of endocrinology, 171(3), 293\u0026ndash;300. https://doi.org/10.1530/EJE-14-0106\u003c/li\u003e\n\u003cli\u003eAl-Zifzaf, D.S., Hamza, S.A., Kaddah, E.A., \u0026amp; Abo-shady, R.A. (2014). Type 2 diabetes raises serum sclerostin levels and disturbs the relation between sclerostin and bone mineral density: a call for caution with antisclerostin therapy in osteoporosis. Egyptian Rheumatology and Rehabilitation, 41, 37-43. DOI https://doi.org/10.4103/1110-161X.128136.\u003c/li\u003e\n\u003cli\u003eNieuwdorp, M., van Haeften, T. W., Gouverneur, M. C., Mooij, H. L., van Lieshout, M. H., Levi, M., Meijers, J. C., Holleman, F., Hoekstra, J. B., Vink, H., Kastelein, J. J., \u0026amp; Stroes, E. S. (2006). Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes, 55(2), 480\u0026ndash;486. https://doi.org/10.2337/diabetes.55.02.06.db05-1103\u003c/li\u003e\n\u003cli\u003eGarsen, M., Lenoir, O., Rops, A. L., Dijkman, H. B., Willemsen, B., van Kuppevelt, T. H., Rabelink, T. J., Berden, J. H., Tharaux, P. L., \u0026amp; van der Vlag, J. (2016). Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disruption of the Glomerular Glycocalyx. Journal of the American Society of Nephrology : JASN, 27(12), 3545\u0026ndash;3551. https://doi.org/10.1681/ASN.2015091070\u003c/li\u003e\n\u003cli\u003eKoos, R., Brandenburg, V., Mahnken, A. H., Schneider, R., Dohmen, G., Autschbach, R., Marx, N., \u0026amp; Kramann, R. (2013). Sclerostin as a potential novel biomarker for aortic valve calcification: an in-vivo and ex-vivo study. The Journal of heart valve disease, 22(3), 317\u0026ndash;325. PMID: 24151757.\u003c/li\u003e\n\u003cli\u003eLeto, G., D\u0026apos;Onofrio, L., Lucantoni, F., Zampetti, S., Campagna, G., Foffi, C., Moretti, C., Carlone, A., Palermo, A., Leopizzi, M., Porta, N., Massucci, M., Lenzi, A., Bertoletti, G. B., Rocca, C. D., \u0026amp; Buzzetti, R. (2019). Sclerostin is expressed in the atherosclerotic plaques of patients who undergoing carotid endarterectomy. Diabetes/metabolism research and reviews, 35(1), e3069. https://doi.org/10.1002/dmrr.3069.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable (1): Clinic-demographic and laboratory data of the studied cohort.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 37px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll subjects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;(DM, non-DN)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroup 2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(DN)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.80 \u0026plusmn; 4.23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11.18 \u0026plusmn; 3.16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.08 \u0026plusmn; 2.29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.381\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7-14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u0026ndash; 15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7-17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender (n, %)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13 (52.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (64.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18 (72.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.339\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12 (48.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9 (36.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7 (28.0%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI SDS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.55 (0.4-1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.48(0.11-1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.53(0.3-0.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.305\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of diabetes (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (3 \u0026ndash; 5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8 (6 \u0026ndash; 11)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum creatinine (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.37 \u0026plusmn; 0.12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.41 \u0026plusmn; 0.15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.39 \u0026plusmn; 0.19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.73\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1 \u0026ndash; 0.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.2 \u0026ndash; 0.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.2 \u0026ndash; 0.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e108.31\u0026plusmn;6.82\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e109.7\u0026plusmn;5.32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.4223\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHbA1c %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 \u0026plusmn; 1.27\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11.13 \u0026plusmn; 1.91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal serum cholesterol (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e100 (50 \u0026ndash; 149)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e86 (60 \u0026ndash; 160)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.946\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum Triglycerides (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e82 (65 \u0026ndash; 113)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e110 (66 \u0026ndash; 124)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.228\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUACR (mg/g creatinine)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.87\u0026plusmn;3.21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e64.33\u0026plusmn;13.45\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum Sclerostin (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13.5 (10.32 \u0026ndash; 15.72)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e33.29 (28.37 \u0026ndash; 38.53)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e90.83 (82.32 \u0026ndash; 115.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.03 \u0026ndash; 19.33\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17.23 \u0026ndash; 60.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e43.63 \u0026ndash; 145.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIMT (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.11 (0.1 \u0026ndash; 0.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.11 (0.1 \u0026ndash; 0.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.1 (0.8 \u0026ndash; 1.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\u0026nbsp;\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1 \u0026ndash; 0.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01 \u0026ndash; 0.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.3 \u0026ndash; 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBMI: body mass index; CIMT: carotid intima media thickness, DM: diabetes mellitus, DN: diabetic nephropathy, eGFR: estimated glomerular filtration ratio, HBA1c: hemoglobin A1c, SD: standard deviation, UACR: urinary albumin creatinine ratio\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (2): Correlation of serum Sclerostin and CIMT with other studied parameters among all participants with T1DM.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll T1DM patients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 50)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003eSerum Sclerostin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003eCIMT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.132\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.371\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.034\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.784\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eDisease duration (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.678**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.617**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eHbA1c%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.426**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.436**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cem\u003e0.002\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eMicroalbuminuria (mg/gm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.798**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.798**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eCholesterol (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.022\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.881\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.022\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.878\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.155\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.284\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.114\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.432\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum Sclerostin (ng/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.66\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026lt;0.001\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIMT (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.66\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCIMT: carotid intima media thickness, DM: diabetes mellitus, HBA1c%: Hemoglobin A1c%, r: Spear-man correlation coefficient.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (3): Correlation of serum Sclerostin and CIMT with other studied parameters among participants with DN.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDN group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSclerostin factor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIMT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003er\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003er\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.405\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eDuration(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.507**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.469**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHbA1c %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.688**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.753**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMicroalbuminuria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.798**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.617**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eCholesterol(mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.672\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.775\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.796\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIMT (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.512\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum Sclerostin level (ng/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.512\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCIMT, carotid intima media thickness; DN, diabetic nephropathy; HBA1c, hemoglobin A1c; TG, triglyceride.\u003c/p\u003e\n\u003cp\u003eP-value \u0026gt; 0.05: Non-significant; P-value \u0026lt; 0.05: Significant; P-value \u0026lt; 0.01: Highly significant; r, Spearman correlation coefficient.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"CIMT, DN, Sclerostin, T1DM","lastPublishedDoi":"10.21203/rs.3.rs-5734283/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5734283/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eChronically uncontrolled diabetes mellitus (DM) is linked to long-term micro and macrovascular adverse outcomes, through speeding up atherosclerosis and peripheral vascular diseases. Owing to the early cardiac and renal involvement, an early diagnostic biomarker is required. Sclerostin is a Wnt-signaling inhibitor, having a pathophysiological role in vasculopathy, and could be used as a vasculopathy marker, nevertheless, few data are available in pediatric patients with type 1 diabetes mellitus (T1DM). We aimed at assessing its serum level, and the relation to diabetic microvascular and macrovascular complications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: a case control study on pediatric and adolescent patients with T1DM, and healthy controls. Patients were divided according to proteinuria into non-diabetic nephropathy (DN), and DN group. Patients’ clinicodemographic, and anthropometric measurements were obtained, with withdrawal of fasting serum lipid profile, kidney function test, and serum sclerostin. Carotid intimal media thickness (CIMT), a marker of subclinical atherosclerosis, was measured.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe included 75 comparable subjects, where median (IQR) serum sclerostin levels was significantly higher in DN, compared to non-DN, and controls [90.83 (82.32 – 115.1), vs 33.29 (28.37 – 38.53), vs 13.5 (10.32 – 15.72) ng/ml respectively, p\u0026lt; 0.001]. Similarly, median (IQR) CIMT was significantly higher in DN, than non-DN and controls [1.1 (0.8 – 1.3), vs 0.11 (0.1 – 0.2), vs 0.11 (0.1 – 0.2) mm, p\u0026lt;0.001]. Serum sclerostin level correlated positively with disease duration, higher HgbA1c%, albuminuria level, and CIMT in all patients. The cut off values of serum sclerostin \u0026gt; 60.0 ng/ml and CIMT \u0026gt;0.3 mm were able to detect DN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Serum Sclerostin levels could serve as a potential biomarker for micro and macrovascular complications in pediatric patients with T1DM.\u003c/p\u003e","manuscriptTitle":"Serum Sclerostin as a Marker of Microvascular and Macrovascular Complications among Children and Adolescents with Type 1 Diabetes Mellitus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-02 18:19:13","doi":"10.21203/rs.3.rs-5734283/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2025-01-30T12:12:21+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-12-30T22:39:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-12-30T19:42:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-12-30T11:22:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-12-30T04:19:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d6025c5a-4030-4e0c-8c58-1d27b881c3ca","owner":[],"postedDate":"January 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T16:01:57+00:00","versionOfRecord":{"articleIdentity":"rs-5734283","link":"https://doi.org/10.1007/s00467-025-06793-3","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2025-05-12 15:57:50","publishedOnDateReadable":"May 12th, 2025"},"versionCreatedAt":"2025-01-02 18:19:13","video":"","vorDoi":"10.1007/s00467-025-06793-3","vorDoiUrl":"https://doi.org/10.1007/s00467-025-06793-3","workflowStages":[]},"version":"v1","identity":"rs-5734283","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5734283","identity":"rs-5734283","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}