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Serum total Osteocalcin level as a vascular marker in elderly patients with metabolic syndrome BY NANY HASAN ASSISTANT PROFESSOR OF INTERNAL MEDICINE GERIATERICS DEPARTMENT ALEXANDRIA UNIVERSITY EGYPT Introduction Metabolic syndrome (MetS) is a major public-health problem and clinical challenge worldwide. Metabolic syndrome is a constellation of interconnected physiological, biochemical, clinical and metabolic factors that directly increases the risk of atherosclerotic cardiovascular diseases, type 2 diabetes mellitus and all-cause mortality. Its main components are: Dyslipidemia, elevation of arterial blood pressure, and dys-regulated glucose homeostasis, while abdominal obesity and/or insulin resistance (IR) have gained increasing attention as the core manifestations of the syndrome. Recently, other abnormalities such as chronic pro-inflammatory and prothrombotic states, non-alcoholic fatty liver disease and sleep apnea have been added to the entity of the syndrome, making its definition even more complex(1). Dysfunctional adipose tissue plays an important role in the pathogenesis of obesityrelated insulin resistance. Both adipose cell enlargement and infiltration of macrophages into adipose tissue result in the release of pro-inflammatory cytokines and promote insulin resistance . Insulin resistance appears to be the primary mediator of metabolic syndrome . The distribution of adipose tissue appears to affect its role in metabolic syndrome. Visceral or intra-abdominal fat correlates with inflammation, whereas subcutaneous fat does not. There are numbers of potential explanations for this, including experimental observations that omental fat is more resistant to insulin and may result in a higher concentration of toxic free fatty acids in the portal circulation. Abdominal fat is known to produce potentially harmful levels of cytokines, such as tumor necrosis factor, adiponectin, leptin, resistin, and plasminogen activator inhibitor(2). The most commonly used criteria for definition of metabolic syndrome at present are from: • The World Health Organization (WHO) • The European Group for the study of Insulin Resistance (EGIR) • The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) • American Association of Clinical Endocrinologists (AACE) • The International Diabetes Federation (IDF) Currently, the two most widely used definitions are those of the NCEP: ATP III and IDF focusing specifically on waist circumference, which is a surrogate measure of central obesity. In contrast, the AACE, WHO and the EGIR definitions are all largely focused on insulin resistance. Prevalence of metabolic syndrome Clearly, the prevalence of MetS varies and depends on the criteria used in different definitions, as well as the composition (sex, age, race and ethnicity) of the population studied. No matter which criteria are used, the prevalence of MetS is high and rising in all western societies, probably as a result of the obesity epidemic. According to National Health and Examination Survey (NHANES) 2003-2006 , approximately 34% of people studied met the NCEP: ATPIII revised criteria for MetS. The prevalence of metabolic syndrome increases with age, with about 40% of people older than 60 years meeting the criteria . Several epidemiological studies have confirmed the increased risk of CVD in individuals with MetS, independently of the diagnostic criteria used. Overall a range of 1.5-3 times greater risk of CVD and CHD mortality has been found in several prospective studies, whereas a recent meta-analysis showed that MetS was associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality.(3-4) The pathophysiology is very complex and has been only partially elucidated. Most patients are : Old Obese Sedentary Have a degree of insulin resistance Stress can also be a contributing factor. The most important factors are: Genetics Aging Diet (particularly sugar-sweetened beverage consumption) Sedentary behavior, or low physical activity Disrupted sleep Mood disorders Psychotropic medication use Excessive alcohol use Osteocalcin Osteocalcin is a non-collagenous, 49 amino acid glutamate-rich polypeptide bone matrix protein with a molecular weight of about 5800 kDa. Osteoblasts produce osteocalcin and incorporate it into the bone matrix. Osteocalcin is released into the circulation from the matrix during bone resorption and, therefore, is considered a marker of bone turnover rather than a specific marker of bone formation . Osteocalcin, has raised much attention as a hormone regulating glucose metabolism and fat mass. Recently, osteocalcin has been recognized as a bone-derived hormone to regulate energy metabolism. Osteocalcin knockout mice exhibited glucose intolerance, increased fat mass, insulin resistance, decreased expression of insulin target genes in liver and muscle, and decreased adiponectin gene expression in adipose tissue, while administration of recombinant osteocalcin increased insulin secretion, decreased blood glycaemia and weaken the development of obesity. (5) Figure 1: Osteocalcin synthesis in osteoblasts. The BGLAP gene encoding osteocalcin is mainly expressed in osteoblasts and to lesser extent odontoblasts. After transcription (which is stimulated by vitamin D) the preproosteocalcin peptide undergoes proteolysis giving rise to a prepeptide (23 aa) and a proosteocalcin peptide (75 aa). The latter can be carboxylated at Glu residues 17, 21, and 24, resulting in formation of Gla residues in a vitamin K dependent process. Generally, this process only occurs in a proportion of newly synthesized pro-osteocalcin. Then Gla and Glu pro-osteocalcin peptides are subjected to a final proteolytic process that produces, respectively, carboxylated and undercarboxylated osteocalcins. Both forms are released from osteoblasts in a process which is calcium dependent. While the carboxylated Gla residues are involved in calcium and hydroxyapatite binding, allowing osteocalcin deposition on mineralized bone matrix, undercarboxylated osteocalcin has a low affinity for hydroxyapatite and is more easily released into the circulation. Osteocalcin undergoes γ-carboxylation. The γ-carboxylated form binds hydroxyapatite and is abundant in bone extracellular matrix. In contrast, the under-carboxylated circulating form has been implicated as a novel hormone and positive regulator of glucose homeostasis. The uOC acts directly on the β-cells to increase their mass and proliferation and therefore increases insulin secretion. Moreover, it influences white adipocytes to induce the expression of genes involved in energy expenditure and to enhance the secretion of adiponectin, thus increasing insulin sensitivity. Apart from its secretion from the osteoblasts, OC is also secreted locally by adipocytes and megakaryocytes. Combining these actions, OC is capable of enhancing the secretion of insulin and increasing insulin sensitivity in both fat and muscle. Endocrine actions of osteocalcin. Circulating osteocalcin and particularly its undercarboxylated fraction (released during active bone resorption) exerts a direct effect on β cells, stimulating insulin production as well as on adipocytes enhancing adiponectin production. Adiponectin itself is able to promote insulin sensitivity. In turn, insulin also acts directly on osteoblast and indirectly on osteoclast. Osteoclast stimulates bone resorption with subsequent release of undercarboxylated osteocalcin in blood circulation. Finally, osteocalcin has a role also on Leydig cells, increasing their activity and testosterone production. Importantly, osteocalcin expression has been described in calcifying vascular smooth muscle cells (VSMCs), although the physiological significance of this observation has remained unclear. Osteocalcin is considered as a novel regulator of osteochondrogenic differentiation of pathologically mineralizing VSMCs, which provides the first evidence that osteocalcin may be an active player in vascular calcification, with its presence in the calcified vasculature, and potentially the circulation, activating novel signaling pathways that promote mineralization. Pathological mineralization of the vasculature has a detrimental effect on cardiovascular function and is associated with increased mortality in patients with aging, atherosclerosis, type 2 diabetes, and chronic kidney disease. Aim of the work We aimed in the that study to analyze the correlation between serum levels of osteocalcin and vascular calcification in elderly persons with metabolic syndrome. Materials and methods The current study included 74 elderly males, 65 years and older who were recruited either from the geriatric outpatient clinic, or hospitalized patients. Participants were divided into two groups; Group (I); 40 elderly male patients satisfied at least three criteria of the metabolic syndrome (MetS), Group (II); 34 healthy elderly males serving as a control group. We used the definition of MetS according to the NCEP-ATP III ; Fasting blood glucose level ≥110 mg/dl, Blood pressure ≥130/85 mmHg, Triglycerides ≥ 150 mg/dl, HDL cholesterol <40 mg/dl , and Waist circumference >102 cm for men. The exclusion criteria included: Presence of any significant liver disease. Renal failure requiring renal-replacement therapy. Patients taking lipid-lowering drugs or any drugs that could influence bone metabolism. Anthropometric measurements (including height and weight) were taken, and the body mass index (BMI) was calculated. Blood samples obtained from all participants after overnight fast for determination of : Total serum cholesterol HDL-cholesterol Serum triglycerides Fasting blood glucose. Serum total osteocalcin (TOC) was measured using an N-MID Osteocalcin ELISA kit (Elecsys, Roche diagnostic Ltd., Switzerland). Ultrasound on the carotid arteries for measuring intima-media thickness. Results 74 elderly males participated in the current study divided into two groups according to the presence or absence of MetS, according to the NCEP-ATP III criteria. Group I; 40 males (62.5%) with MetS, their mean age was 70.70 ± 4.98 years, compared to 34 agematched males (37.5%) without MetS, served as a control group, their mean age was70.76 ± 4.59 years, with no statistical significant difference between both groups. (P =0.954) Group I patients exhibited significantly higher BMIs, compared to group II, with a mean of 30.90 ± 1.68 Kg/m2 in group I , and 26.33 ± 2.0 Kg/m2 in group II (p<0.001). Group I patients had significantly higher waist circumference, fasting blood sugar, Triglycerides, blood pressure, and lower HDL-ch , compared to group II subjects. Also, total cholesterol was significantly higher in group I patients than group II subjects. Patients of group I had significantly lower levels of total Osteocalcin (TOC), compared with subjects in group II . Results of carotid Doppler revealed mean intima-media thickness of 1.07 ± 0.16 mm in group I, and 0.70 ± 0.07 mm in group II, with a statistical significant difference between both groups (p<0.001). Also group I patients had significantly higher plaques number compared to group II subjects (p<0.001). Age Systolic Diastolic FBG Normal Abnormal TG Normal Abnormal HDL Normal Abnormal Total ch. Normal Abnormal WC Normal Abnormal Group I(MetS) Group II(Controls) (n = 40) (n = 34) 70.70 ± 4.98 70.76 ± 4.59 154.37 ± 7.78 132.79 ± 6.30 92.50 ± 4.24 78.09 ± 4.27 140.82 ± 32.54 103.18 ± 4.12 6(15.0%) 34(100.0%) 34(85.0%) 0(0.0%) 153.87 ± 21.75 107.35 ± 14.86 13(32.5%) 34(100.0%) 27(67.5%) 0(0.0%) 47.30 ± 7.25 60.65± 6.28 34(85.0%) 34(100.0%) 6(15.0%) 0(0.0%) 200.0(88.0 – 240.0) 102.0 (89.0 – 188.0) 18(45.0%) 34(100.0%) 22(55.0%) 0(0.0%) 88.94 ± 2.81 103.78 ± 6.60 34(100.0%) 16(40.0%) 0(0.0%) 24(60.0%) P 0.954 <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* BMI Normal Over weight Obese OCN Normal Abnormal IMT Carotid plaques No 1 2 30.90 ± 1.68 0(0.0%) 14(35.0%) 26(65.0%) 26.33 ± 2.0 10(29.4%) 23(67.6%) 1(2.9%) <0.001* 5.79 ± 1.77 0(0.0%) 40(100.0%) 1.07 ± 0.16 30.20 ± 8.69 33(97.1%) 1(2.9%) 0.70 ± 0.07 <0.001* 5(12.5%) 23(57.5%) 12(30.0%) 31(91.2%) 3(8.8%) 0(0.0%) Statistically significant at p ≤ 0.05 <0.001* <0.001* <0.001* <0.001* OCN Group I(MetS) Group II(Controls) r p r p Systolic -0.127 0.434 -0.196 0.266 Diastolic -0.102 0.532 -0.120 0.501 FBG 0.050 0.760 -0.128 0.470 TG 0.057 0.725 0.042 0.815 HDL 0.116 0.474 0.322 0.064 WC -0.029 0.858 -0.273 0.118 OCN Group I(MetS) Group II(Controls) r p r p TG -0.469* 0.005 0.042 0.815 Total Ch. -0.366* 0.020 0.057 0.725 0.116 0.474 0.322 0.064 HDL r: Pearson coefficient *: Statistically significant at p ≤ 0.05 Australian study showed that serum osteocalcin levels predicted all-cause and CVD-related mortality in community-dwelling older men.(6) Saleem et al. determined that serum TOC is negatively associated with MetS in both blacks and non-Hispanic whites .(7) Oosterwerff et al. found that plasma TOC was inversely associated with MetS in a community-dwelling cohort of older persons in the Netherlands, and reported that the subjects with the lowest quartile of TOC concentrations had an approximately 3.7-fold higher risk of MetS than did the subjects with the highest quartile.(8) Also, Yeap et al. reported that men with lower serum TOC concentrations have a higher risk of MetS. (9) In a study by Bezerra dos Santos et al, the mean osteocalcin was significantly lower in patients with MetS and decreased significantly with the rise in the number of criteria for diagnosis of MetS. Serum osteocalcin was lower in patients with body mass index (BMI) ≥25 and FPG ≥100 mg/dl, and in hypertensive and diabetic patients, and was inversely associated with BMI, waist circumference, FPG, and systolic blood pressure.(10) There is evidence to show the influence of bone proteins on cardiovascular disease. During atherogenesis, bone matrix proteins, including osteocalcin, may have a regulatory role in the atherosclerotic calcification process. Recent evidence suggests that osteoblast-like cells are present in the vasculature and capable of calcifying vascular cells. Furthermore, paracrine regulators of bone metabolism such as osteocalcin is also present in atherosclerotic arteries. Thus, the vascular microenvironment possesses mechanisms similar to those in bone tissues to maintain mineral homeostasis. Osteocalcin-knockout mice develop extensive calcification of arteries that rapidly becomes lethal, suggesting that osteocalcin has an anti-mineralization role in the artery. In humans, osteocalcin is detected in human carotid arteries from endarterectomy samples. Thus, osteocalcin could play a pivotal role in not only bone mineralization but also vascular wall calcification. However, at present, little is known about whether serum osteocalcin secreted from osteoblasts in bone or osteoblast-like cells in vessels actually could modulate atherosclerosis. Thus, further studies are needed to clarify the pathophysiological processes underlying the relationship between serum osteocalcin level and atherosclerosis parameters. Conclusion Our study indicated that serum osteocalcin levels were significantly associated with carotid atherosclerosis in patients with metabolic syndrome. This may reflect the role of osteocalcin as a circulating endocrine factor which regulates glucose metabolism and thereby cardiovascular risk in patients with metabolic syndrome. Prospective studies are needed to assess the time course and relevance of serum osteocalcin in the development of atherosclerosis in patients with metabolic syndrome. References 1. S. M. Grundy, J. I. Cleeman, S. R. Daniels et al., “Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement,” Circulation 2005; 112(17):2735-52. 2. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008 May 23; 94(2):206-18. 3. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH: The metabolic syndrome. Endocr Rev 2008, 29:777-822. 4. Hollman G, Kristenson M: The prevalence of the metabolic syndrome and its risk factors in a middleaged Swedish population--mainly a function of overweight? Eur J Cardiovasc Nurs 2008, 7:21-6. 5. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J. The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int 2000; 11(6):2-17. 6. Yeap BB, Chubb SA, Flicker L, McCaul KA, Ebeling PR, Hankey GJ, Beilby JP, Norman PE: Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The Health In Men Study. Osteoporos Int 2012, 23:599–606. 7. U. Saleem, T. H. Mosley Jr., and I. J. Kullo, “Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome,” Arteriosclerosis, Thrombosis, and Vascular Biology 2010; 30 (7): pp. 1474-8. 8. M. M. Oosterwerff, N. M. van Schoor, P. Lips, et al., “Osteocalcin as a predictor of the metabolic syndrome in older persons: a population-based study,” Clinical Endocrinology 2013; 78(2):pp. 242–7. 9. B. B. Yeap, S. A. Chubb, L. Flicker, et al., “Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The Health in Men Study,” Osteoporosis International 2012; 23(2): pp. 599–606. 10. Bezerra dos Santos M, Magalhães MM, Diniz ET, Lucena CS, Griz L, Bandeira F. Metabolic syndrome and central fat distribution are related to lower serum osteocalcin concentrations. Annals of Nutrition & Metabolism 2013; 62(3):183-8.