Abstract
Purpose
Osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC) are matrix glycoproteins which mediate bone mineralization; moreover, their effects on glucose/insulin homeostasis have recently been demonstrated. Higher circulating OPN and OPG levels have been associated with the presence of insulin resistance, atherosclerosis and coronary heart disease. No data are available on contextual changes of these markers in type 2 diabetes mellitus (T2DM). Therefore, aims of this study were to evaluate serum OPN, OPG and OC levels in T2DM patients and their clinical correlates.
Methods
We recruited 83 consecutive T2DM patients referring to our diabetes outpatient clinics at Sapienza, University of Rome, and 71 non-diabetic sex and age-comparable subjects as a control group. Study population underwent metabolic characterization and carotid ultrasound for intima–media thickness measurement. Plasma OPN, OPG and OC were measured by MILLIPLEX Multiplex Assays Luminex.
Results
T2DM patients had significantly higher circulating OPN and OPG levels than controls (14.3 ± 13.6 vs 10.6 ± 13.7 ng/ml p < 0.001, 0.70 ± 0.60 vs 0.54 ± 4.1 ng/ml, p = 0.02) while OC levels were similar in the two cohorts (6.35 ± 5.8 vs 7.80 ± 7.0 ng/ml, p = n.s). OPN and OPG positively correlated with greater systolic blood pressure (SBP) values, HOMA-IR and HOMA-β, and with the presence of dyslipidemia and carotid atherosclerosis. The association between greater OPN and OPG levels and SBP was independent from possible confounders (both p = 0.01).
Conclusions
Circulating OPN and OPG levels are increased in T2DM patients and identify a particularly unfavourable metabolic profile, mostly expressed by higher SBP. Bone peptides may represent novel markers of vascular stress and accelerated atherosclerosis in diabetes, constituting a possible tool for cardiovascular risk stratification in diabetes.
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References
Chapman J, Miles PD, Ofrecio JM, Neels JG, Yu JG, Resnik JL, Wilkes J, Talukdar S, Thapar D, Johnson K, Sears DD (2010) Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice. PLoS One 5:e13959. https://doi.org/10.1371/journal.pone.0013959
Kiefer FW, Neschen S, Pfau B, Legerer B, Neuhofer A, Kahle M, Hrabé de Angelis M, Schlederer M, Mair M, Kenner L, Plutzky J, Zeyda M, Stulnig TM (2011) Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice. Diabetologia 54:2132–2142. https://doi.org/10.1007/s00125-011-2170-0
Morisawa T, Nakagomi A, Kohashi K, Kosugi M, Kusama Y, Atarashi H, Shimizu W (2015) Osteoprotegerin is associated with endothelial function and predicts early carotid atherosclerosis in patients with coronary artery disease. Int Heart J 56:605–612. https://doi.org/10.1536/ihj.15-150
García-Martín A, Rozas-Moreno P, Reyes-García R, Morales-Santana S, García-Fontana B, García-Salcedo JA et al (2012) Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 97(1):234–241
Morales-Santana S, García-Fontana B, García-Martín A, Rozas-Moreno P, García-Salcedo JA, Reyes-García R et al (2013) Atherosclerotic disease in type 2 diabetes is associated with an increase in sclerostin levels. Diabetes Care 36(6):1667–1674
Novo-Rodríguez C, García-Fontana B, Luna-Del Castillo JD, Andújar-Vera F, Ávila-Rubio V, García-Fontana C et al (2018) Circulating levels of sclerostin are associated with cardiovascular mortality. PLoS One 13(6):e0199504
Rubin MR, Silverberg SJ (2004) Vascular calcification and osteoporosis—the nature of the nexus. J Clin Endocrinol Metab 89:4243–4245
Singh DK, Winocour P, Summerhayes B, Kaniyur S, Viljoen A, Sivakumar G, Farrington K (2012) Prevalence and progression of peripheral vascular calcification in type 2 diabetes subjects with preserved kidney function. Diabetes Res Clin Pract 97:158–165. https://doi.org/10.1016/j.diabres.2012.01.038
Panizo S, Cardus A, Encinas M, Parisi E, Valcheva P, López-Ongil S, Coll B, Fernandez E, Valdivielso JM (2009) RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res 104:1041–1048. https://doi.org/10.1161/CIRCRESAHA.108.189001
Pollack RM, Donath MY, LeRoith D, Leibowitz G (2016) Anti-inflammatory agents in the treatment of diabetes and its vascular complications. Diabetes Care 39:S244–252. https://doi.org/10.2337/dcS15-3015
Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM (1994) Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res 74:214–224
Lewis JR, Lim WH, Ueland T, Wong G, Zhu K, Lim EM, Bollerslev J, Prince RL (2015) Elevated circulating osteoprotegerin and renal dysfunction predict 15-year cardiovascular and all-cause mortality: a prospective study of elderly women. PLoS One 7:e0134266. https://doi.org/10.1371/journal.pone.0134266
Callegari A, Coons ML, Ricks JL, Rosenfeld ME, Scatena M (2014) Increased calcification in osteoprotegerin-deficient smooth muscle cells: dependence on receptor activator of NF-κB ligand and interleukin 6. J Vasc Res 51:118–131. https://doi.org/10.1159/000358920
Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, Stolina M, Kostenuik PJ, Demer LL (2008) Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(−/−) mice. Circulation 117:411–420
Zoch ML, Clemens TL, Riddle RC (2016) New insights into the biology of osteocalcin. Bone 82:42–49. https://doi.org/10.1016/j.bone.2015.05.046
Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M et al (2003) Global diabetic retinopathy project group. Proposed international clinical retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110:1677–1682
Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41
Daniele G, Winnier D, Mari A, Bruder J, Fourcaudot M, Pengou Z et al (2018) The potential role of the osteopontin-osteocalcin-osteoprotegerin triad in the pathogenesis of prediabetes in humans. Acta Diabetol 55(2):139–148
Berezin AE, Kremzer AA (2013) Circulating osteopontin as a marker of early coronary vascular calcification in type two diabetes mellitus patients with known asymptomatic coronary artery disease. Atherosclerosis 229:475–481. https://doi.org/10.1016/j.atherosclerosis.2013.06.003
Yan X, Sano M, Lu L, Wang W, Zhang Q, Zhang R, Wang L, Chen Q, Fukuda K, Shen W (2010) Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 9:70. https://doi.org/10.1186/1475-2840-9-70
Barchetta I, Alessandri C, Bertoccini L, Cimini FA, Taverniti L, Di Franco M, Fraioli A, Baroni MG, Cavallo MG (2016) Increased circulating osteopontin levels in adult patients with type 1 diabetes mellitus and association with dysmetabolic profile. Eur J Endocrinol 174:187–192. https://doi.org/10.1530/EJE-15-0791
Zwakenberg SR, van der Schouw YT, Schalkwijk CG, Spijkerman AMW, Beulens JWJ (2018) Bone markers and cardiovascular risk in type 2 diabetes patients. Cardiovasc Diabetol 17(1):45
Knudsen ST, Foss CH, Poulsen PL, Andersen NH, Mogensen CE, Rasmussen LM (2003) Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications. Eur J Endocrinol 149:39–42
Duan P, Yang M, Wei M, Liu J, Tu P (2017) Serum osteoprotegerin is a potential biomarker of insulin resistance in Chinese postmenopausal women with prediabetes and type 2 diabetes. Int J Endocrinol 2017:8724869. https://doi.org/10.1155/2017/8724869
Sanchez-Enriquez S, Ballesteros-Gonzalez IT, Villafán-Bernal JR, Pascoe-Gonzalez S, Rivera-Leon EA, Bastidas-Ramirez BE, Rivas-Carrillo JD, Alcala-Zermeno JL, Armendariz-Borunda J, Llamas-Covarrubias IM, Zepeda-Moreno A (2017) Serum levels of undercarboxylated osteocalcin are related to cardiovascular risk factors in patients with type 2 diabetes mellitus and healthy subjects. World J Diabetes 8:11–17. https://doi.org/10.4239/wjd.v8.i1.11
Vigili de Kreutzenberg S, Fadini GP, Guzzinati S, Mazzucato M, Volpi A, Coracina A, Avogaro A (2015) Carotid plaque calcification predicts future cardiovascular events in type 2 diabetes. Diabetes Care 38:1937–1944. https://doi.org/10.2337/dc15-0327
Bessueille L, Fakhry M, Hamade E, Badran B, Magne D (2015) Glucose stimulates chondrocyte differentiation of vascular smooth muscle cells and calcification: a possible role for IL-1β. FEBS Lett 589:2797–2804. https://doi.org/10.1016/j.febslet.2015.07.045
Rozas Moreno P, Reyes García R, García-Martín A, Varsavsky M, García-Salcedo JA, Muñoz-Torres M (2013) Serum osteoprotegerin: bone or cardiovascular marker in type 2 diabetes males? J Endocrinol Invest 36:16–20. https://doi.org/10.3275/8285
Gaudio A, Privitera F, Pulvirenti I, Canzonieri E, Rapisarda R, Fiore CE (2014) Relationships between osteoprotegerin, receptor activator of the nuclear factor kB ligand and serum levels and carotid intima-media thickness in patients with type 2 diabetes mellitus. Panminerva Med 56:221–225
Jung CH, Lee WY, Kim SY, Jung JH, Rhee EJ, Park CY, Mok JO, Oh KW, Kim CH, Park SW, Kim SW (2010) The relationship between coronary artery calcification score, plasma osteoprotegerin level and arterial stiffness in asymptomatic type 2 DM. Acta Diabetol 47:145–152. https://doi.org/10.1007/s00592-009-0154-z
Poulsen MK, Nybo M, Dahl J, Hosbond S, Poulsen TS, Johansen A, Høilund-Carlsen PF, Beck-Nielsen H, Rasmussen LM, Henriksen JE (2011) Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus. Cardiovasc Diabetol 10:76. https://doi.org/10.1186/1475-2840-10-76
Anand DV, Lahiri A, Lim E, Hopkins D, Corder R (2006) The relationship between plasma osteoprotegerin levels and coronary artery calcification in uncomplicated type 2 diabetic subjects. J Am Coll Cardiol 47:1850–1857
Anand DV, Lim E, Darko D, Bassett P, Hopkins D, Lipkin D, Corder R, Lahiri A (2007) Determinants of progression of coronary artery calcification in type 2 diabetes role of glycemic control and inflammatory/vascular calcification markers. J Am Coll Cardiol 50:2218–2225
Leslie WD, Rubin MR, Schwartz AV, Kanis JA (2007) Type 2 diabetes and bone. J Bone Miner Res 27:223–2237
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This work was funded by research grants from the Sapienza Ateneo Scientific Research.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Barchetta, I., Ceccarelli, V., Cimini, F.A. et al. Impaired bone matrix glycoprotein pattern is associated with increased cardio-metabolic risk profile in patients with type 2 diabetes mellitus. J Endocrinol Invest 42, 513–520 (2019). https://doi.org/10.1007/s40618-018-0941-x
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DOI: https://doi.org/10.1007/s40618-018-0941-x