Correlation of Plasma and Salivary Osteocalcin Levels with Nascent Metabolic Syndrome Components with and Without Pre/Diabetes Biochemical Parameters
Main Article Content
Keywords
adipolin, cathepsin, FGF1 (Fibroblast growth factor 1), ghrelin, irisin, klotho, LBP (lipopolysaccharide binding protein), Leptin, Osteocalcin, adiposity and atherogenicity indices, cardiometabolic risk, nascent metabolic syndrome and prediabetes
Abstract
Objectives: This study aimed to compare and correlate plasma and salivary levels of cardiometabolic risk biomarkers’ of pharmacotherapy (appraised using colorimetric assays), adiposity, and atherogenicity indices. Methods: 61 Nascent MetS subjects vs. 30 lean normoglycemic and healthy controls were recruited in Family Medicine outpatient clinics/Jordan University Hospital (a referral medical center). Fasting blood and saliva specimens were collected. Clinical and anthropometric variables were determined along with atherogenecity and adiposity indices. Results: Among nascent MetS (metabolic syndrome) recruits, almost half were normoglycemic, 43% were prediabetic and 8% were diabetic. Pronouncedly Glycemic (FPG and Alc) and lipid parameters (TG, HDL-C and non-HDL-C), adiposity indices (BMI, WHR, WtHR, Conicity-index, BAI, LAP, VAI) and atherogenicity indices (AIP, TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C and TG/HDL-C) were higher in the nascent MetS group (P<0.05 vs. controls). Markedly among the plasma cardiometabolic risk biomarkers (P<0.05 vs. controls) in the nascent MetS group, adipolin, cathepsin S, ghrelin, irisin, LBP, leptin, and osteocalcin were higher but plasma FGF1 levels were oddly lower. Significantly (P<0.05 vs. controls) nascent MetS –linked salivary levels of adipolin and LBP were higher as opposed to the lower cathepsin S. Only osteocalcin, amongst 9 metabolic risk biomarkers studied, had remarkably significant correlation between plasma and saliva levels, in both total sample and MetS patients (P<0.05). Markedly in the nascent MetS only group, both plasma and salivary osteocalcin correlated with FPG and A1c (P<0.05); salivary osteocalcin correlated with BMI and LAP (P<0.05). Likewise, in the total sample plasma osteocalcin correlated significantly with BMI, BAI, WHt R, SBP, DBP, TG, LAP, VAI, TG/HDL-C and AIP (P<0.05), while salivary osteocalcin had substantial correlations only with FPG and A1c (P<0.05). Conclusion: Association of nascent MetS-related plasma and salivary osteocalcin levels and clinical characteristics and indices propagate salivary osteocalcin as a non-invasive marker for clinical control of MetS-/preDM.
References
2. Shrestha S, Pokhrel S, Poudel A, et al. Implication of salivary biochemical parameters for diagnosis and prognosis of type 2 diabetes mellitus. International Journal of Analytical Chemistry. 2022;1781613. https://doi.org/10.1155/2022/1781613.
3. Zyśk B, Ostrowska L, Smarkusz-Zarzecka J. Salivary adipokine and cytokine levels as potential markers for the development of obesity and metabolic disorders. International Journal of Molecular Sciences. 2021; 22(21):11703. https://doi.org/10.3390/ijms222111703
4. Wetterö J, Jönsson F, von Löhneysen S, et al. Pentraxin-3 detected in human saliva shows limited correlation with biomarkers associated with systemic inflammation. ActaPathologica, Microbiologica, etImmunologicaScandinavica, (APMIS) 2021; 129(6):304-313. https://doi.org/10.1111/apm.13136.
5. Techatanawat S, Surarit R, Chairatvit K, et al. Salivary and serum cystatin SA levels in patients with type 2 diabetes mellitus or diabetic nephropathy. Archives of Oral Biology. 2019; 104:67-75.https://doi.org/10.1016/j.archoralbio.2019.05.020
6. KemerDoğan ES, Duran N. Is periodontal inflamed surface area associated with serum and salivary levels of IL-1β, visfatin, and omentin-1 in overweight/obese patients? Clinical Oral Investigations. 2022; 26:5351–5358.https://doi.org/10.1007/s00784022-04502-0
7. Gomathi GD, Gopalakrishnan S, Sudhakar U, et al. Effects of non-surgical periodontal therapy on saliva and gingival crevicular fluid levels of chemerin in periodontitis subjects with and without type 2 diabetes mellitus. Cureus. 2023; 15(1). https://doi.org/10.7759/cureus.33388.
8. Polizzi A, Torrisi S, Santonocito S, et al. Influence of myeloperoxidase levels on periodontal disease: an applied clinical study.Applied Sciences. 2020; 10(3):1037. https://doi.org/10.3390/app10031037
9. Anil S, Vellappally S, Preethanath RS, et al. Hepatocyte growth factor levels in the saliva and gingival crevicular fluid in smokers with periodontitis. Disease Markers. 2014;146974. https://doi.org/10.1155/2014/146974.
10. Waluś-Miarka M, Trojak A, Miarka P,et al. Correlates of pentraxin 3 serum concentration in men and women with type 2 diabetes. Innate Immunity. 2020; 26(5):351-357.https://doi.org/10.1177/1753425919891628.
11. Lee CH, Hsu KY, Lin CJ. IDF21-0219 Association of plasma and salivary cystatin-c levels and clinical characteristics in type 2 diabetes. Diabetes Research & Clinical Practice. 2022; 186(Suppl.1):109637. https://doi.org/10.1016/ j.diabres.2022.109637
12. (a). Aydin S, Aydin S, Kuloglu T, et al. Alterations of irisin concentrations in saliva and serum of obese and normal-weight subjects, before and after 45 min of a Turkish bath or running. Peptides. 2013; 50:13-18. https://doi.org/10.1016/ j.peptides.
2013.09.011; (b). Aydin S, Aydin S, Kobat MA, et al. A Decreased saliva/serum irisin concentration in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology. Peptides.2014;56:141-147. https://doi.org/10.1016/j.peptides.2014.04.002.
13. Koopaie M, Salamati M, Montazeri R, et al. Salivary cystatin S levels in children with early childhood caries in comparison with caries-free children; statistical analysis and machine learning. BMC Oral Health. 2021; 21: 650. https://doi.org/10.1186/s12903-021-02016-x
14. Mamali I, Roupas ND, Armeni AK, et al. Measurement of salivary resistin, visfatin and adiponectin levels. Peptides. 2012;33(1):120-124. https://doi.org/10.1016/j.peptides.2011.11.007
15. Brum RS, Duarte PM, Canto GL, et al. Biomarkers in biological fluids in adults with periodontitis and/or obesity: A metaanalysis.Journal of Indian Society of Periodontology. 2020; 24(3):191–215.https://doi.org/10.4103/jisp.jisp_512_19.
16. Tierney C, Bazou D, Lê G, et al. Saliva-omics in plasma cell disorders- Proof of concept and potential as a non-invasive tool for monitoring disease burden. Journal of Proteomics. 2021; 231:104015. https://doi.org/10.1016/ j.jprot.2020.104015.
17. (a).Beshay M, Rhee CM, Kalantar-Zadeh K. Novel monitoring of renal function and medication levels in saliva and capillary blood of patients with kidney disease. Current Opinion of Nephrology & Hypertension. 2022; 31(1):100-108.https://doi.org/10.1097/ MNH.0000000000000764; (b). Loo JA, Yan W, Ramachandran P, et al. Comparative human salivary and plasma proteomes. Journal of Dental Research. 2010; 89(10):1016–1023. https://doi.org/10.1177/ 0022034510380414.
18. (a).Srinivasan M, Meadows ML, Maxwell L. Assessment of salivary adipokinesresistin, visfatin, and ghrelin as type 2 diabetes mellitus biomarkers. Biochemistry Research International. 2018; 7463796; https://doi.org/10.1155/2018/ 7463796; (b).Srinivasan M, Blackburn C, Mohamed M, et al. Literature-based discovery of salivary biomarkers for type 2 diabetes mellitus.Biomarker Insights. 2015; 10:39–45. https://doi.org/10.4137/BMI.S22177.
19. (a).Fadaei R, Moradi N, Kazemi T, et al. Decreased serum levels of CTRP12/adipolin in patients with coronary artery disease in relation to inflammatory cytokines and insulin resistance. Cytokine. 2019; 113: 326–331. https://doi.org/10.1016/j.cyto.2018.09.019; (b). Alipoor E, Yaseri M, Mehrdadi P, et al. The relationship between serum adipokines and glucose homeostasis in normal-weight and obese patients on hemodialysis: a preliminary study. International Urology and Nephrology. 2020; 52(11): 2179–2187. https://doi.org/10.1007/s11255-020-02582-z.
20. (a).Rauner M, Föger-Samwald U, Kurz MF, et al. Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture. Bone. 2014; 64:281–287. https://doi.org/10.1016/j.bone.2014.04.022; (b). Karimkhanloo H, Keenan SN, Sun, et al. Circulating cathepsin S improves glycaemic control in mice. Journal of Endocrinology. 2021; 248(2):167–179.https://doi.org/10.1530/JOE-20-0408.
21. Chen L, Lu B, Yang Y, et al. Elevated circulating cathepsin S levels are associated with metabolic syndrome in overweight and obese individuals. Diabetes/Metabolism Research and Reviews. 2019; 35(3):e3117. https://doi.org/10.1002/dmrr.3117.
22. (a). Nies VJM, Sancar G, Liu W. Fibroblast Growth Factor Signaling in Metabolic Regulation. Front Endocrinol. (Lausanne) 2016; 6:193. https://doi.org/10.3389/fendo.2015.00193; (b). Fan L, Ding L, Lan J, et al. Fibroblast growth factor-1 improves insulin resistance via repression of JNK-mediated inflammation. Frontiers in Pharmacology.2019; 10:1478. https://doi.org/10.3389/fphar.2019.01478
23. Słotwińska SM. Ghrelin and oral diseases. Central-European Journal of Immunology. 2020; 45(4):433–438.https://doi.org/10.5114/ ceji.2020.103415
24. (a).Senesi P, Luzi L, Terruzzi I. Adipokines, myokines, and cardiokines: the role of nutritional interventions. International Journal of Molecular Sciences. 2020; 21(21): 8372. https://doi.org/10.3390/ijms21218372; (b) Binay Ç, Paketçi C, Güzel S, et al. Serum irisin and oxytocin levels as predictors of metabolic parameters in obese children. Journal of Clinical Research in Pediatric Endocrinology. 2017; 9(2): 124–131. https://doi.org/10.4274/jcrpe.3963
25. (a).Biyik I, Erten O, Isiklar O, et al. Comparison of serum human Klotho levels and thiol/disulfide homeostasis in women with polycystic ovary syndrome and in healthy women. Taiwanese Journal of Obstetrics &Gynecology. 2021; 60(3):487–491.https://doi.org/ 10.1016/j.tjog.2021.03.017; (b). Frohlich J, Chaldakov GN, Vinciguerra M. Cardio- and NeurometabolicAdipobiology:Consequences and Implications for Therapy. International Journal of Molecular Sciences. 2021; 22(8):4137. https://doi.
org/10.3390/ijms22084137
26. Wolf EJ, Morrison FG, Sullivan DR, et al. The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging. Brain, Behavior, and Immunity. 2019; 80:193-203.https://doi.org/10.1016/j.bbi.2019.03.007.
27. (a)Gonzalez-Quintela A, Alonso M, Campos J, et al. Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS One. 2013; 8(1):e54600. https://doi.org/10.1371/ journal. pone.0054600; (b). Jialal I, Devaraj S, Bettaieb A, et al. Increased adipose tissue secretion of Fetuin-A, lipopolysaccharidebinding protein and high-mobility group box protein 1 in metabolic syndrome. Atherosclerosis. 2015; 241(1):130–137. https://doi.org/10.1016/j.atherosclerosis.2015.04.814.
28. Kheirandish-Gozal L, Peris E, Wang Y, et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. Journal of Clinical Endocrinology & Metabolism. 2014; 99(2): 656–663.https://doi.org/10.1210/jc.2013-3327
29. (a).López-Jaramillo P, Gómez-Arbeláez D, López-López J, et al. The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Hormone Molecular Biology and Clinical Investigation. 2014; 18(1):37–45.https://doi.org/10.1515/hmbci-2013-0053; (b).Jialal I, Devaraj S. Subcutaneous adipose tissue biology in metabolic syndrome. Hormone Molecular Biology and Clinical Investigation. 2018; 33(1). https://doi.org/10.1515/hmbci-2017-0074; (c).Ghadge AA, Khaire AA. Leptin as a predictive marker for metabolic syndrome. Cytokine. 2019; 121: 154735. https://doi.org/10.1016/j.cyto.2019.154735; (d).Correia ML, Rahmouni K. Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome. Diabetes & Obesity Metabolism. 2006; 8(6):603–610. https://doi.org/10.1111/j.1463-1326.2005.00562.x; (e). de Luis DA, Perez Castrillón JL, Dueñas A. Leptin and obesity. Minerva Medica. 2009; 100(3):229-236.
30. Mizokami A, Kawakubo-Yasukochi T, Hirata M. Osteocalcin and its endocrine functions. Biochemical Pharmacology. 2017; 132:1–8. https://doi.org/10.1016/j.bcp.2017.02.001.
31. Guney G, Sener-Simsek B, Tokmak A, et al. Assessment of the relationship between serum vitamin D and osteocalcin levels with metabolic syndrome in non-osteoporotic postmenopausal women. Geburtshilfe Frauenheilkunde 2019; 79(3): 293–299. https://doi.org/10.1055/a-0767-6572.
32. Riquelme-Gallego B, García-Molina L, Cano-Ibáñez N, et al. Circulating undercarboxylated osteocalcin as estimator of cardiovascular and type 2 diabetes risk in metabolic syndrome patients. Scientific Reports. 2020; 10:1840. https://doi.org/10.1038/ s41598-020-58760-733. International diabetes Federation (IDF). Worldwide definition of the metabolic syndrome. The IDF consensus worldwide definition of the Metabolic Syndrome 2006:1e19.
34. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021; 44(Suppl.1):S15-S33. https://doi.org/10.2337/dc21-S002. Erratum in: Diabetes Care. 2021; 44(9):2182.
35. Snouper A, Kasabri V, Bulatova N, et al. Plasma carnitine, choline, γ-butyrobetaine, and trimethylamine n-oxide, but not zonulin, are reduced in overweight/obese patients with pre/diabetes or impaired glycemia. International Journal of Diabetesin Developing Countries. 2022. https://doi.org/10.1007/s13410-022-01088-x
36. Bergman RN, Stefanovski D, Buchanan TA, et al. A better index of body adiposity. Obesity (Silver Spring). 2011; 19(5):1083-9. https://doi.org/10.1038/oby.2011.38.
37. Dobiášová M, Frohlich J. The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FERHDL). Clinical Biochemistry.2001; 34:583–588. https://doi.org/10.1016/s0009-9120(01)00263-6
38. Alberti KG, Eckel RH, Grundy SM, et al.International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120(16):1640-5. https://doi.org/10.1161/CIRCULATIONAHA. 109.192644.7S.
39. Chan YH. Biostatistics 104: Correlational analysis. Singapore Medical Journal. 2003; 44(12):614-619.
40. (a).Desai GS, Mathews ST. Saliva as a non-invasive diagnostic tool for inflammation and insulin resistance. World Journal of Diabetes. 2014; 5(6): 730-738. https://doi.org/10.4239/wjd.v5.i6.730; (b).Kasabri V, Shawakri E, Akour A, et al. Cross-sectional correlates of increased IL-18 but reduced fetuin-A and oxytocin with adiposity and blood indices in metabolic syndrome patients with and without prediabetes. Therapeutic Advances in Endocrinology and Metabolism. 2018; 9(12):329-338.https://doi.org/10.1177/ 2042018818788802; (c).Grewen KM, Davenport RE, Light KC. An investigation of plasma and salivary oxytocin responses in breast- and formula-feeding mothers of infants. Psychophysiology. 2010; 47:625-632. https://doi.org/10.1111/j.1469-8986. 2009.00968.x; (d).Huffmeijer R, Alink LR, Tops M, et al. Salivary levels of oxytocin remain elevated for more than two hours after intranasal oxytocin administration. NeuroEndocrinology Letters. 2012; 33:21-25.
41. Bhandari R, Bakermans-Kranenburg MJ, van der Veen R, et al. Salivary oxytocin mediates the association between emotional maltreatment and responses to emotional infant faces. Physiology & Behavior. 2014;131:123-128.https://doi.org/10.1016/j.physbeh.2014.04.028
42. (a).Kasabri V, Al-Ghareeb MI, Saleh MI, et al. Proportional correlates of adipolin and cathepsin S in metabolic syndrome patients with and without prediabetes. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2019;13(4):2403–2408.
https://doi.org/10.1016/ j.dsx.2019.06.010; (b).Mehrdadi P, KolahdouzMohammadi R, Alipoor E, et al. The Effect of Coenzyme Q10 supplementation on circulating levels of novel adipokineadipolin/CTRP12 in overweight and obese patients with type 2 diabetes. Experimental & Clinical Endocrinology & Diabetes. 2017; 125(3):156–162.https://doi.org/10.1055/s-0042-110570.
43. (a).Jobs E, Risérus U, Ingelsson E, et al. Serum cathepsin S is associated with decreased insulin sensitivity and the development of type 2 diabetes in a community-based cohort of elderly men. Diabetes Care. 2013; 36(1): 163–165. https://doi.org/10.2337/dc12-0494; (b).Rathnayake N, Buhlin K, Kjellström B, et al. Saliva and plasma levels of cardiac-related biomarkers in postmyocardial infarction patients. Journal of Clinical Periodontology. 2017; 44(7):692–699. https://doi.org/10.1111/jcpe.12740.
44. (a).Saber GY, Kasabri V, Saleh MI, et al. Increased irisin versus reduced fibroblast growth factor1 (FGF1) in relation to adiposity, atherogenicity and hematological indices in metabolic syndrome patients with and without prediabetes. Hormone Molecular Biology and Clinical Investigation. 2019; 38(1): 20180063. https://doi.org/10.1515/hmbci-2018-0063; (b).Wang S, Yang Q, Yu S, eta l. Fibroblast growth factor 1 levels are elevated in newly diagnosed type 2 diabetes compared to normal glucose tolerance controls. Endocrine Journal. 2016; 63(4):359–365. https://doi.org/10.1507/endocrj.EJ15-0627; (c).Wang A, Yan X,
Zhang C, et al. Characterization of fibroblast growth factor 1 in obese children and adolescents. Endocrine Connections. 2018;7(8):932–940. https://doi.org/10.1530/EC-18-0141.
45. (a).AbuZayed R, Bulatova N, Kasabri V, et al. Correlates of zinc finger BED domain-containing protein 3 and ghrelin in metabolic syndrome patients with and without prediabetes. Hormone Molecular Biology and Clinical Investigation. 2019; 37(3):/j/hmbci.2019.37.issue-3/hmbci-2018-0052/hmbci-2018-0052.xml. https://doi.org/10.1515/hmbci-2018-0052; (b). Aydin S. A comparison of ghrelin, glucose, alpha-amylase and protein levels in saliva from diabetics. Journal of Biochemistry and Molecular Biology. 2007; 40(1):29–35. https://doi.org/10.5483/bmbrep.2007.40.1.029.
46. Benedix F, Westphal S, Patschke R, et al. Comparison of serum and salivary ghrelin in healthy adults, morbidly obese, and patients with metastatic carcinoma. Obesity Surgery. 2011; 21: 1265-1271.https://doi.org/10.1007/s11695-010-0161-8.
47. (a).Duffles LF, Hermont AP, Abreu LG, et al. Association between obesity and adipokines levels in saliva and gingival crevicular fluid: A systematic review and meta-analysis. Journal of Evidence-Based Medicine. 2019; 12(4):313–324. https://doi.org/10.1111/ jebm.12363; (b).Crabtree DR, Buosi W, Fyfe CL, et al. Salivary ghrelin response to drinks varying in protein content and quantity and association with energy intake and appetite. Physiology & Behavior. 2021; 242:113622. https://doi.org/10.1016/ j.physbeh.2021.113622.
48. Kahwaji R, Kasabri V, Bulatova N, et al. Evaluation of correlations of plasma levels of oxytocin, omentin-1 and irisin in diabetic and non-diabetic metabolic syndrome patients: a cross sectional study in Jordan. Jordan Medical Journal. 2017; 51(3): 97-810.https://doi.org/10.1016/j.dsx.2016.08.008
49. Tabak O, Simsek G, Erdenen F, Sozer V, Hasoglu T, Gelisgen R, Altunoglu E, Muderrisoglu C, Senyigit A, Uzun H. The relationship between circulating irisin, retinol binding protein-4, adiponectin and inflammatory mediators in patients with metabolic syndrome. Archives of Endocrinology and Metabolism. 2017; 61(6):515-523. https://doi.org/10.1590/2359-3997000000289.
50. (a).Tang L, Tong Y, Zhang F, et al. The association of circulating irisin with metabolic risk factors in Chinese adults: a crosssectional community-based study. BMC Endocrine Disorders. 2019; 19(1):147.https://doi.org/10.1186/s12902-019-0479-8; (b).Hassan II, Hassan AB, Rajab HA, et al. Association of irisin and oxidative stress with biochemical parameters in patients with metabolic syndrome. Hormone Molecular Biology and Clinical Investigation. 2019; 39(1). https://doi.org/10.1515/
hmbci-2019-0009.
51. (a).Yosaee S, Basirat R, Hamidi A, et al. Serum irisin levels in metabolically healthy versus metabolically unhealthy obesity: A case-control study. Medical Journal of the Islamic Republic of Iran. 2020; 34:46. https://doi.org/10.34171/mjiri.34.46; (b).Park K, Ahn CW, Park JS, et al. Circulating myokine levels in different stages of glucose intolerance. Medicine (Baltimore). 2020; 99(8):e19235. https://doi.org/10.1097/MD.0000000000019235
52. (a).Tan X, Hu W, Yang S, et al. Association of metabolic syndrome components with circulating levels of cytokine clusters in young women. Endocrine Connections. 2021; 10(1):66–75. https://doi.org/10.1530/EC-20-0569; (b).Hirsch HJ, Gross I, Pollak Y, et al. Irisin and the metabolic phenotype of adults with Prader-Willi Syndrome. PLoS One. 2015; 10(9):e0136864. https://doi.org/10.1371/journal.pone.0136864.
53. (a).Khan SU, Ghafoor S, Khaliq S, et al. Salivary Irisin and periodontal clinical parameters in patients of chronic periodontitis and healthy individuals: A novel salivary myokine for periodontal disease. Journal of Pakistan Medical Association. 2022; 72(1):27-33. https://doi.org/10.47391/JPMA.01367;(b).Altay DU, Korkmaz M, Ergun S, et al. Salivary irisin: potential inflammatory biomarker in recurrent apthous stomatitis patients. European Review for Medical and Pharmacological Sciences. 2021; 25(5):2252-2259. https://doi.org/10.26355/eurrev_202103_25257.
54. (a)Saito Y, Nakamura T, Ohyama Y, et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochemical and Biophysical Research Communications. 2000; 276(2):767–772. https://doi.org/10.1006/bbrc.2000.3470; (b).Luo L, Hao Q, Dong B, et al. The Klotho gene G-395A polymorphism and metabolic syndrome in very elderly people. BMC Geriatrics. 2016; 16:46. https://doi.org/10.1186/s12877-016-0221-6.
55. (a).Kim HJ, Lee J, Chae DW, et al. Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study. BMC Nephrology. 2019; 20:119. https://doi.org/10.1186/s12882-019-1297-y; (b). SochaBanasiak A, Michalak A, Pacześ K, et al. Klotho and fibroblast growth factors 19 and 21 serum concentrations in children and adolescents with normal body weight and obesity and their associations with metabolic parameters. BMC Pediatrics.
2020; 20(1):294. https://doi.org/10.1186/s12887-020-02199-2; (c).Liu YC, Tsai JP, Wang LH, et al. Positive correlation of serum fibroblast growth factor 23 with peripheral arterial stiffness in kidney transplantation patients. Clinica Chimica Acta(International Journal of Clinical Chemistry.) 2020; 505:9–14. https://doi.org/10.1016/ j.cca.2020.02.014
56. Al-Qudah SA , Kasabri V , Saleh MI , et al. Cross-sectional correlates of nesfatin and lipopolysaccharide binding protein in metabolic syndrome patients with and without prediabetes. Hormone Molecular Biology and Clinical Investigation. 2018;36(3). https://doi.org/10.1515/hmbci-2018-0035.
57. (a).Jialal I, Rajamani U, Adams-Huet B, et al. Circulating pathogen-associated molecular pattern - binding proteins and High Mobility Group Box protein 1 in nascent metabolic syndrome: implications for cellular Toll-like receptor activity. Atherosclerosis. 2014; 236(1): 182–187. https://doi.org/10.1016/j.atherosclerosis.2014.06.022; (b). Liu X, Lu L, Yao P, et al. Lipopolysaccharide
binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese. Diabetologia. 2014; 57(9):1834–1841. https://doi.org/ 10.1007/s00125-014-3288-7.
58. Lim PS, Chang YK, Wu TK. Serum lipopolysaccharide-binding protein is associated with chronic inflammation and metabolic syndrome in hemodialysis patients. Blood Purification. 2019; 47(1-3): 28–36.https://doi.org/10.1159/000492778.
59. (a)Al-Nouaaimi M, Kasabri V, Bulatova N, et al. Evaluation of the correlation of oxytocin plasma levels and metabolic syndrome biomarkers (leptin, adiponectin and resistin) in newly diagnosed type 2 diabetes patients in Jordan: a cross sectional study. Jordan Journal of Pharmaceutical Sciences. 2016; 9(2):115-128; (b).Al-Amodi HS, Abdelbasit NA, Fatani SH, et al. The effect of obesity and components of metabolic syndrome on leptin levels in Saudi women. Diabetes & Metabolic Syndrome. 2018; 12(3):357–364. https://doi.org/10.1016/j.dsx.2017.12.030; (c). Lee KW, Shin D. Prospective Associations of serum adiponectin, leptin, and leptin-adiponectin ratio with incidence of metabolic syndrome: the Korean genome and epidemiology study. International Journal of Environmental Research and Public Health. 2020; 17(9):3287. https://doi.org/10.3390/ ijerph17093287.
60. (a).Ibrahim Abdalla MM, Siew Choo S. Salivary leptin level in young adult males and its association with anthropometric measurements, fat distribution and muscle mass. European Journal of Endocrinology. 2018; 14(2):94-98. https://doi.org/10.17925/ EE.2018.14.2.94; (b).Thanakun S, Watanabe H, Thaweboon S, et al. Comparison of salivary and plasma adiponectin and leptin in patients with metabolic syndrome. Diabetology & Metabolic Syndrome. 2014; 6:19. https://doi.org/10.1186/1758-5996-6-19
61. Kasabri V, Albsoul-Younes A, Suyagh M, et al. Sirtuin 1, but not osteocalcin, correlates with lipid accumulation product, visceral adiposity and atherogenicity indices in newly diagnosed prediabetes-metabolic syndrome patients. Romanian Journal of Diabetes Nutrition and Metabolic Diseases. 2020; 27(3):220-236. https://doi.org/10.46389/rjd-2020-1034
62. Bador KM, Wee LD, Halim SA, et al. Serum osteocalcin in subjects with metabolic syndrome and central obesity. Diabetes & Metabolic Syndrome. 2016; 10 (1 Suppl. 1):S42–S45. https://doi.org/10.1016/j.dsx.2015.09.009
63. (a).Saleem U, Mosley TH, Kullo IJ. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30:1474–1478. https://doi.
org/10.1161/ ATVBAHA.110.204859; (b).Bae SJ, Choe JW, Chung YE, et al. The association between serum osteocalcin levels and metabolic syndrome in Koreans. Osteoporosis International. 2011; 22: 2837–2846. https://doi.org/10.1007/s00198-010-1504-y; (c). García-Martín A, Cortés-Berdonces M, Luque-Fernández I, et al. Osteocalcin as a marker of metabolic risk in healthy postmenopausal women. Menopause. 2011; 18:537–541. https://doi.org/10.1097/gme.0b013e3181f8565e; (d). Lee SW, Jo HH, Kim MR, et al. Association between obesity, metabolic risks and serum osteocalcin level in postmenopausal women. Gynecological Endocrinology. 2012; 28:472–477. https://doi.org/10.3109/09513590.2011.633660
64. (a). Movahed A, Larijani B, Nabipour I, et al. Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism. The Journal of Bone and Mineral Metabolism. 2012; 30: 683–691. https://doi.org/10.1007/s00774-012-0367-z; (b).Gursoy UK, Liukkonen J, Jula A, et al. Associations between Salivary Bone Metabolism Markers and Periodontal Breakdown. Journal of Periodontology. 2016; 87(4):367-75. https://doi.org/10.1902/jop.2015.150399.
65. (a).Cutando A, López-Valverde A, Gómez-de-Diego R, et al. Effect of gingival application of melatonin on alkaline and acid phosphatase, osteopontin and osteocalcin in patients with diabetes and periodontal disease. Medicina Oral, Patología Orally Cirugía Bucal. 2013; 18(4):e657–e663. https://doi.org/10.4317/medoral.18832; (b).Miricescu D, Totan A, Calenic B, et al.
Salivary biomarkers: relationship between oxidative stress and alveolar bone loss in chronic periodontitis. Acta Odontologica Scandinavica. 2014; 72(1):42–47. https://doi.org/10.3109/00016357.2013.795659.
66. (a).Rao PV, Reddy AP, Lu X, et al. Proteomic identification of salivary biomarkers of type-2 diabetes. Journal of Proteomic Research. 2009; 8(1):239–245. https://doi.org/10.1021/pr8003776; (b).Williamson S, Munro C, Pickler R, et al. Comparison of biomarkers in blood and saliva in healthy adults. Nursing Research & Practice. 2012; 2012:246178. https://doi.org/10.1155/2012/246178.