|Year : 2017 | Volume
| Issue : 4 | Page : 176-180
Relationship between subclinical hypothyroidism and serum osteoprotegerin level in type 2 diabetic patients
Eman H El-Adawy MD 1, Gehan A Shaker2, Amal Seleem3
1 Department of Internal Medicine, Endocrinology Unit, Specialized Medical Hospital, Egypt
2 Department of Physiology, Faculty of Medicine, Mansour University, Mansoura, Egypt
3 Department of Biochemistry, Faculty of Medicine, Mansour University, Mansoura, Egypt
|Date of Submission||12-Jun-2017|
|Date of Acceptance||25-Jun-2017|
|Date of Web Publication||4-Dec-2017|
Eman H El-Adawy
Department of Internal Medicine, Endocrinology Unit, Specialized Medical Hospital, Faculty of Medicine, Elgomhoria St, Mansoura, 35516
Source of Support: None, Conflict of Interest: None
Background Subclinical hypothyroidism (SCH) and osteoprotegerin (OPG) are associated with higher risks of cardiovascular disorders in patients with type 2 diabetes mellitus (T2DM). It is unknown whether diabetic patients with SCH have elevated OPG compared with those with euthyroid and, if so, whether SCH independently associated with OPG level.
Objective The objective was to study the association between SCH and serum OPG level among Egyptian adults with newly diagnosed T2DM.
Patients and methods One hundred and fifty patients with newly diagnosed T2DM and 150 healthy controls matched for sex and age were included in the study. Serum OPG, thyroid-stimulating hormone (TSH), free thyroxine, free triiodothyronine, blood glucose, lipid profile, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and anthropometric measurements were assessed for all participants.
Results The prevalence of SCH and elevated level of OPG in the diabetic patients were higher than healthy controls (17.3 vs. 4%, P<0.001; and 14 vs. 4.7%, P=0.02; respectively). Diabetics with SCH demonstrated significantly higher HOMA-IR, serum TSH, and OPG compared with diabetics without SCH. Serum TSH was significantly correlated with total cholesterol (P=0.05), fasting insulin (P=0.01), HOMA-IR (P=0.01), and OPG (P=0.005). Moreover, serum OPG was correlated with waist circumference (P=0.01), fasting insulin (P=0.05), and HOMA-IR (P=0.02). Multiple logistic regression analysis revealed that SCH was associated with serum level of OPG independently of the other significant variables (β=2.49, P=0.01).
Conclusion T2DM patients with SCH demonstrate higher level and independent association with serum OPG than those with euthyroid. This result might add new information about the causal relationship between SCH and cardiovascular disorders in such a population.
Keywords: cardiovascular disorders, osteoprotegerin, subclinical hypothyroidism, type 2 diabetes
|How to cite this article:|
El-Adawy EH, Shaker GA, Seleem A. Relationship between subclinical hypothyroidism and serum osteoprotegerin level in type 2 diabetic patients. Egypt J Intern Med 2017;29:176-80
|How to cite this URL:|
El-Adawy EH, Shaker GA, Seleem A. Relationship between subclinical hypothyroidism and serum osteoprotegerin level in type 2 diabetic patients. Egypt J Intern Med [serial online] 2017 [cited 2018 Mar 24];29:176-80. Available from: http://www.esim.eg.net/text.asp?2017/29/4/176/219796
| Background|| |
Development and progression of type 2 diabetes mellitus (T2DM) is considered as a serious global health burden and closely associated with macrovascular and microvascular complications that negatively affected all-cause and cardiovascular (CV) mortality ,,.
Osteoprotegerin (OPG) is a secretory glycoprotein that is related to the tumor necrosis factor receptor family and included in the regulation of bone metabolism, vascular tone enhancement, endothelium regeneration, and vascular calcification processes ,. It has been identified as an independent risk factor of cardiovascular disorders (CVD) in patients with T2DM, metabolic syndrome, chronic renal disease, and polycystic ovary syndrome ,,,, all of which were closely related to endothelial dysfunctions ,.
Patients with T2DM are more likely to have subclinical hypothyroidism (SCH) when compared with the healthy population ,,. SCH is usually asymptomatic and diagnosed by elevated serum thyroid-stimulating hormone (TSH) with normal free thyroxine and free triiodothyronine levels . Several clinical studies have shown an independent association between SCH and CVD ,, and between serum level of OPG and CVD in T2DM patients ,,; however, whether SCH is associated with serum level of OPG in T2DM has not been studied before. Moreover, because there is no enough data on serum OPG levels in SCH, it is of great importance to evaluate their possible association. Therefore, we aimed to study the association between SCH and serum OPG among Egyptian adults with newly diagnosed T2DM and also their association with other metabolic risk factors.
| Patients and methods|| |
This prospective study included a total of 150 patients with newly diagnosed T2DM before starting antidiabetic medications (64 male and 86 female), aged 45.5±5.1 years, selected from the Outpatient Clinics of Diabetes and Endocrinology Unit at Specialized Medical Hospital, Mansoura University, Faculty of Medicine, Egypt, during the period from February 2016 to March 2017. One hundred and fifty healthy controls matched for sex and age with exclusion criteria similar to the diabetic patients were also included. Informed consents were obtained from all participants, and approval was given by the ethics committee of our institution.
Full history taking and clinical examination were performed for all participants. We used standardized techniques in the assessment of height, weight, BMI, and waist circumference (WC). BMI was calculated as weight in kilograms divided by height in meters squared (kg/m2). Blood pressure was taken in the sitting position using a random-zero sphygmomanometer. SCH was defined as TSH above the high-reference range (4 μU/ml according the method used in the present study). Exclusion criteria included hypertension, heart failure, acute coronary syndrome, or those taking drugs affecting thyroid or vascular functions (e.g. antiplatelet agent, lipid-lowering agents, antioxidant supplements, immunosuppressants, bisphosphonate, amiodarone, or lithium), smoking, hepatic disorders, connective tissue diseases, malignancy, infection, pregnancy, and female on birth control pills or hormone replacement therapy.
Blood glucose was determined using a commercially available kit, Cobas (Integra-400) (supplied by Roche Diagnostic, Basel, Germany). Serum triglyceride, total cholesterol (TC), and high-density lipoprotein cholesterol were measured using commercially available kits. Low-density lipoprotein cholesterol was estimated according to the method by Friedewald et al. . Measurement of fasting serum insulin was done by a solid-phase, enzyme-labeled chemiluminescent immunometric assay using Immulite analyzer (IMMULITE 2000, Diagnostic Products Corp., IL, USA). Homeostasis model assessment of insulin resistance (HOMA-IR) was measured with the following formula: HOMA-IR=fasting insulin (µU/ml)×fasting glucose (mmol/l)/22.5 . Hemoglobin A1c (HbA1c) was measured on a DCA 2000 analyzer, fast ion exchange resin supplied by human (Germany) with the reference range of 4.4–6.4%. Serum free triiodothyronine, free thyroxine, and TSH were assayed by electrochemiluminescence immunoassay, using Elecsys 2010 (Roche Diagnostic). Serum OPG was measured in duplicate by enzyme-linked immunosorbent assay with the Duoset kit (DY805; R&D Systems, Minneapolis, Minnesota, USA) as recommended by the manufacturer. The intra-assay and interassay coefficients of variation were 3–9 and 3–10%, respectively.
Data analysis was performed using SPSS statistical package version 17 (SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean±SD for continuous data, proportion, and frequency for categorical data, and median (minimum to maximum) for skewed data. Comparison of two groups was done with Student’s t-test and Mann–Whitney U-test. A χ2-test was used in categorical data. Relationship between different items was determined using Pearson’s and Spearman’s correlations. Multiple logistic regression analysis was performed to evaluate the association of SCH with OPG. OPG, fasting insulin, and HOMA-IR were entered in the regression model. P value 0.05 or less was considered significant.
| Results|| |
Clinical and laboratory characteristics of the 150 newly diagnosed diabetic patients and 150 controls were determined in [Table 1]. Diabetic individuals had significantly higher WC, BMI, blood pressure, blood glucose, HbA1c, fasting insulin, and HOMA-IR, TC, triglyceride, and low-density lipoprotein cholesterol than controls, whereas high-density lipoprotein cholesterol was significantly lower in diabetics than in controls. Serum levels of TSH and OPG were significantly higher in diabetic patients than in healthy controls (5.3±1.9 vs. 2.4±1.2, P<0.001; and 3.04±1.6 vs. 2.5±0.9, P=0.001; respectively). Prevalence of SCH in diabetics was 17.3% (26/150) compared with 4% (6/150) in controls (P<0.001). The prevalence of elevated level of OPG in diabetic patients was 14% (21/150) compared with 4.7% (7/150) in controls (P=0.02).
Patients with newly diagnosed T2DM were divided into two groups: diabetics with SCH and diabetics without SCH. Diabetics with SCH are characterized by significantly higher fasting insulin, HOMA-IR, serum TSH (6.75±1.9 vs. 3.2±0.9 mU/ml, P<0.001), and serum OPG levels (2.98±1.09 vs. 2.41±0.95, P=0.01) than diabetics without SCH, whereas WC, BMI, blood pressure, blood glucose, HbA1c, and lipid profile were not different in the two groups ([Table 2]).
|Table 2 Comparison between diabetics with and without subclinical hypothyroidism|
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Serum TSH was significantly associated with fasting insulin (r=0.19, P=0.01), HOMA-IR (r=0.22, P=0.01), TC (r=0.17, P=0.05), and OPG (r=0.19, P=0.01) ([Table 3]). Moreover, OPG level was significantly correlated with WC (P=0.01), fasting insulin (P=0.05), HOMA-IR (P=0.02), and TSH level.
|Table 3 Correlation of thyroid-stimulating hormone with the studied variables and osteoprotegerin in diabetics|
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Using multiple logistic regression analysis, we found that SCH was associated with OPG independent of the other significant variables: fasting insulin and HOMA-IR (β=2.49, odds ratio: 4.63, 95% confidence interval: 1.46–14.75, P=0.01) ([Table 4]). Furthermore, there was an insignificant association between TSH and serum OPG in healthy controls (r=0.06, P=0.4).
|Table 4 Multiple logistic regression analysis of thyroid-stimulating hormone with the significant variables|
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| Discussion|| |
This study investigated the association between SCH and serum level of OPG in patients with newly diagnosed T2DM. It has been known that SCH exhibits a close link to CVD in T2DM ,,, but the exact mechanism is still inconclusive. Our main finding of the independent association between SCH and elevated serum level of OPG might add more information about the causal relationship between SCH and CVD in such a population.
The association between T2DM and SCH is well recognized, with a prevalence of 10–24% ,,,. In the present study, prevalence of SCH in diabetics was 17.3% compared with 4% in controls. We found a significant association between SCH and TC, fasting insulin, and HOMA-IR. These results are in agreement with those of Chubb et al.  who reported that a slight variation in TSH level could exert a marked effect on lipid concentrations in adults with DM. Furthermore, Maratou et al.  proved that patients with SCH have insulin resistance that is comparable to that of the patients with hypothyroidism. These findings indicate that patients with T2DM are more prone to have vascular complications when hypothyroidism associates with diabetes, which is in agreement with the finding of many researches ,,.
Thus, the presence of SCH can aggravate the classical risk factors such as dyslipidemia, hypertension, and insulin resistance and lead to an increased CV risk in such patients. Moreover, the increase in plasma blood glucose and HbA1c leads to glucotoxicity and more atherogenic dyslipidemia, which contributes to two-fold to four-fold excess risk of CVD in diabetics.
Our result of higher prevalence of elevated serum level of OPG in the diabetic patients in this study compared with controls is in agreement with previous researches ,,; furthermore, we demonstrated that OPG level was significantly associated with high TC, fasting insulin, and HOMA-IR. These results are in parallel with those of Bernardi et al. , who observed that serum OPG was correlated positively with insulin resistance in T2DM. Moreover, OPG was found as a powerful marker of macrovascular and microvascular complications and could be utilized for risk stratification in the general population and T2DM with CVD beyond classic CV risk factors ,, However, evidence regarding elevated OPG level as a marker of CV events in diabetics without known CV disease still remains inconclusive and requires further investigations ,.
In the current study, we found that newly diagnosed diabetics with SCH demonstrated higher serum level of OPG than those with euthyroid. These data were in good agreement with a previous report demonstrating higher serum OPG in hypothyroid patients than in controls . Moreover, multiple logistic regression analysis demonstrated that SCH was independently associated with OPG level. This interaction between lower thyroid function and higher serum level of OPG might be a key determinant for a more CV risk in these populations.
The mechanisms of SCH-related CVD in diabetic patients is suggested to be related to aggravation of the classical risk factors such as hypertension, dyslipidemia, insulin resistance , and impaired nitric oxide availability and reduced endothelium-dependent vasodilation . Therefore, the finding of our study suggested that the association between SCH and high serum level of OPG might have an important role in the etiopathological relationship between SCH and development of CVD in patients with T2DM.
The limitation of our study is that analysis of thyroid hormones and serum levels of OPG were measured at a single time point. Follow-up thyroid function are needed to confirm the association between serum level of OPG and the clinical course of SCH. However, the strength of the study is its case control design, which can establish the causal association between SCH and serum OPG level in T2DM.
| Conclusion|| |
Our findings suggest that diabetics with SCH revealed an independent association between TSH and serum level of OPG, which might be considered as a causal link between SCH and CVD in T2DM patients. Screening and treatment of SCH may be required and it could help in the management of diabetic vascular complications. Future studies also are required to confirm this association and to test the effect of thyroxin therapy on serum level of OPG in such populations.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 137:49–103.
Straka RJ, Liu LZ, Girase PS, DeLorenzo A, Chapman RH. Incremental cardiovascular costs and resource use associated with diabetes: osteoprotegerin in type 2 diabetes mellitus 63 an assessment of 29,863 patients in the US managed-care setting. Cardiovasc Diabetol 2009; 1:53–58.
Wu W, Ren M, Cheng H, Li Y, Qi Y-Q, Yang C, Yan L. Prevention of macrovascular disease in patients with short-duration type 2 diabetes by multifactorial target control: an 8-year prospective study. Endocrine 2014; 47:485–492.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R et al.
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89:309–319.
Pérez de Ciriza C, Lawrie A, Varo N. Osteoprotegerin in cardiometabolic disorders. Int J Endocrinol 2015; 1:15.
Tousoulis D, Siasos G, Maniatis K, Oikonomou E, Kioufis S, Zaromitidou M et al.
Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease. Int J Cardiol 2013; 1924:1924–1928.
Stępień E, Wypasek E, Stopyra K, Konieczyńska M, Przybyło M, Pasowicz M. Increased levels of bone remodeling biomarkers (osteoprotegerin and osteopontin) in hypertensive individuals. Clin Biochem 2011; 826:831–844.
Makarović S, Makarović Z, Steiner R, Mihaljević I, Milas-Ahić J. Osteoprotegerin and vascular calcification: clinical and prognostic relevance. Coll Antropol 2015; 461:8–39.
Kadoglou NP, Gerasimidis T, Golemati S, Kapelouzou A, Karayannacos PE, Liapis CD. The relationship between serum levels of vascular calcification inhibitors and carotid plaque vulnerability. J Vasc Surg 2008; 47:55–62.
Bernardi S, Fabris B, Thomas M, Toffoli B, Tikellis C, Candido R et al.
Osteoprotegerin increases in metabolic syndrome and promotes adipose tissue proinflammatory changes. Mol Cell Endocrinol 2014; 394:13–20.
Suliburska J, Bogdanski P, Gajewska E, Kalmus G, Sobieska M, Samborski W. The association of insulin resistance with serum osteoprotegerin in obese adolescents. J Physiol Biochem 2013; 847:853–869.
Bharat DH, Gangte D, Lalnunpui , Premchand , Devi I, Singh W. Thyroid status in diabetes mellitus. J Glycomics Lipidomics 2013; 3:1.
Palma CC, Marco P, Veronica GN, Eliete LS, Maria FB, Luiz CP et al.
Prevalence of thyroid dysfunction in patients with diabetes mellitus. Diabetol Metab Syndr 2013; 5:58.
Laloo D, Salam R. Thyroid dysfunction in type 2 diabetes mellitus: a retrospective study. Ind J Endocrinol Metabol 2012; 16:S334–S335.
Simon HS, Georg B, Leonidas HD, Fabio M, Robin PP, Salman R. et al.
2013 ETA Guideline: management of Subclinical hypothyroidism. Eur Thyroid J 2013; 2:215–228.
Chen HS, Wu TE, Jap TS, Lu RA, Wang ML, Chen RL. et al.
.. Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in type 2 diabetic patients. Diabetic Med 2007; 24:1336–1344.
Auer J, Berent R, Weber T, Lassnig E, Eber B. Thyroid function is associated with the presence and severity of coronary atherosclerosis. Clin Cardiol 2003; 26:569–573.
Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metabol 2003; 88:2438–2444.
Alkaç C, Alkaç B, Akbaş F, Aral H, Karagöz Y, Altunoğlu EG. Osteoprotegerin as a marker of atherosclerosis in type 1 and type 2 diabetic Patients. Turk J Med Sci 2015; 1306:1311–1345.
Esteghamati A, Sheikhbahaei S, Hafezi-Nejad N, Mousavizadeh M, Noshad S, Larimi NG et al.
Serum osteoprotegerin in relation to metabolic status, severity, and estimated risk of subsequent coronary heart Disease. Arch Iran Med 2014; 596:601–617.
Hosbond SE, Diederichsen AC, Saaby L, Rasmussen LM, Lambrechtsen J, Munkholm H et al.
Can osteoprotegerin be used to identify the presence and severity of coronary artery disease in different clinical settings? Atherosclerosis 2014; 236:230–236.
Friedewald WT, Levy RT, Fredrickson DS. Estimation of the concentration of low- density lipoprotein cholesterol without the use of preparative ultracentrifuge. Clin Chem 1972; 18:499.
Matthews DR, Hosler JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 1985; 412:419–428.
Chubb SA, Davis WA, Davis TM. Interactions among thyroid function, insulin sensitivity, and serum lipid concentrations: the Fremantle diabetes study. J Clin Endocrinol Metab 2005; 5317:20–90.
Maratou E, Hadjidakis DJ, Kollias A, Tsegka K, Peppa M, Alevizaki M et al.
Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol 2009; 160:785–790.
Berezin AE, Kremzer AA, Martovitskaya YV, Samura TA, Berezina TA, Zulli A et al.
The utility of biomarker risk prediction score in patients with chronic heart failure. Int J Clin Exp Med 2015; 18255:66.
Grais IM, Sowers JR. Thyroid and the heart. Am J Med 2014; 127:691–698.
Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F et al.
Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007; 167:1526–1532.
Evrard S, Delanaye P, Kamel S, Cristol JP, Cavalier E. Vascular calcification: from pathophysiology to biomarkers. Clin Chim Acta 2015; 401:14–438.
Pepene CE, Ilie IR, Marian I, Duncea I. Circulating osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in polycystic ovary syndrome: relationships to insulin resistance and endothelial dysfunction. Eur J Endocrinol 2011; 61:68–164.
Nagasaki T, Inaba M, Jono S, Hiura Y, Tahara H, Shirakawa K et al.
Increased levels of serum osteoprotegerin in hypothyroid patients and its normalization with restoration of normal thyroid function. Eur J Endocrinol 2005; 152:347–353.
Vargas F, Moreno JM, Rodriguez-Gomez I, Wangensteen R, Osuna A, Alvarez-Guerra M, Garcia-Estan J. Vascular and renal function in experimental thyroid disorders. Eur J Endocrinol 2006; 154:197–212.
Biondi B, Galderisi M, Pagano L, Sidiropulos M, Pulcrano M, De A et al.
Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency. Eur J Endocrinol 2009; 161:323–329.
[Table 1], [Table 2], [Table 3], [Table 4]