Plasma Osteoprotegerin Concentrations in Type 2 Diabetic Patients and its Association with Neuropathy

Abstract

Background and Aims: To investigate the association of plasma osteoprotegerin (OPG) levels with diabetic neuropathy.

Methods: Forty-two diabetic patients (21 female and 21 male) and twenty-four non-diabetic healthy control subjects (12 female and 12 male) were included in the study. All consecutive diabetic patients who came for routine follow-up at our outpatient clinic were invited to participate in this clinical study. We studied EMG and neuropathy symptom score in all study subjects. Fasting plasma glucose, HbA1 _c , hs-CRP, OPG levels and lipid profile were measured for each subject.

Results: Serum fasting glucose, HbA1c, HOMA-IR, total cholesterol, triglyserid, LDL-Cholesterol, HDL-Cholesterol, lipoprotein (a), apolipoprotein-b, hs-CRP, OPG levels, and neuropathy symptom score were statistically higher in diabetic patients than in healthy control subjects. Plasma OPG levels was statistically higher in diabetic patients than it was in nondiabetic control subjects. However, plasma OPG levels were not significantly different between diabetic patients without neuropathy and healthy control subjects. On the other hand, OPG levels were statistically higher in diabetic patients with neuropathy than in patients without neuropathy. In addition to that serum fasting glucose, HbA1c, hs-CRP, diabetes duration, neuropathy symptom score were statistically higher in diabetic patients with neuropathy than they were in patients without neuropathy. In total group of subjects, plasma OPG levels were correlated significantly with age, diabetes duration, HbA1c, total cholesterol, HDL-cholesterol, lipoprotein (a), apolipoprotein b, hs-CRP. In diabetic patients, plasma OPG correlated significantly with age, diabetes duration, neuropathy symptom score, HbA1c, lipoprotein (a), apolipoprotein b levels.

Conclusions: The major findings of this study were that the plasma OPG concentrations were higher in type 2 diabetic patients than OPG concentrations in healthy control subjects and they were positively correlated with diabetic neuropathy. This finding supports the growing concept that OPG acts as an important regulator in the development of vascular dysfunction in diabetes.

Key words

osteoprotegerin - peripheral neuropathy - metabolic control - diabetes duration

References

• 1 Simonet WS, Lacey DL, Dunstan CR. et al . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.  Cell. 1997;  89 309-319
• 2 Emery JG, MacDonnell P, Burke MB. et al . Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.  J Biol Chem. 1998;  273 14363-14367
• 3 Zhang J, Fu M, Myles D. et al . PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways.  FEBS Letters. 2002;  521 180-184
• 4 Malyankar UM, Scatena M, Suchland KL. et al . Osteoprotegerin is an alpha beta 3-induced, NF-kappa B-dependent survival factor for endothelial cells.  J Biol Chem. 2000;  275 20959-20962
• 5 Schoppet M, Al Fakhri N, Franke FE. et al . Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Monckeberg's sclerosis and atherosclerosis.  J Clin Endocrinol Metab. 2004;  89 4104-4112
• 6 Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.  Circulation Research. 2004;  95 1046-1057
• 7 Jono S, Ikari Y, Shioi A. et al . Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease.  Circulation. 2002;  106 1192-1194
• 8 Browner WS, Lui Ly, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women.  J Clin Endocrinol Metab. 2001;  86 631-637
• 9 Secchiero P, Corallini F, Pandolfi A. et al . An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction.  Am J Pathol. 2006;  169 2236-2244
• 10 Rasmussen LM, Tarnow L, Hansen TK. et al . Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients.  Eur J Endocrinol. 2006;  154 75-81
• 11 Anand DV, Lahiri A, Lim E. et al . The relationship between plasma osteoprotegerin levels and coronary artery calcification in uncomplicated type 2 diabetic subjects.  J Am Coll Cardiol. 2006;  47 1850-1857
• 12 Ross R. Atherosclerosis is an inflammatory disease.  Am Heart J. 1999;  138 419-420
• 13 Ben Tal CE, Hohensinner PJ, Kaun C. et al . Statins decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro.  Biochem Pharmacol. 2007;  73 77-83
• 14 Rasmussen LM, Hansen PR, Nabipour MT. et al . Diverse effects of inhibition of 3-hydroxy- 3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells.  Biochem J. 2001;  360 363-370
• 15 Nellemann B, Gormsen LC, Dollerup J. et al . Simvastatin reduces plasma osteoprotegerin in type 2 diabetic patients with microalbuminuria.  Diabetes care. 2007;  30 3122-3124
• 16 Knudsen ST, Foss CH, Poulsen PL. et al . Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications.  Europ J Endocrinol. 2003;  149 39-42
• 17 Sultan A, Avignon A, Galtier F. et al . Osteoprotegerin, thiazolidinediones treatment, and silent myocardial ischemia in type 2 diabetic patients.  Diabetes Care. 2008;  31 593-595
• 18 Abbott CA, Vileikyte L, Williamson S. et al . Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration.  Diabetes Care. 1998;  21 1071-1075
• 19 Dyck PJ, Kratz KM, Karnes JL. et al . The prevalence bystaged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study.  Neurology Apr. 1993;  43 ((4)) 817-824
• 20 Maser RE, Steenkiste AR, Dorman JS. et al . Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study.  Diabetes. 1989;  38 1456-1461
• 21 American Diabetes Association, American Academy of Neurology. . Report and recommendations of the San Antonio Conference on Diabetic Neuropathy (Consensus Statement).  Diabetes Care. 1988;  11 592-597
• 22 Senol MG, Saracoglu M. Significance of neuropathy symptom and disability scores in the diagnosis of neuropathy in diabetic patients.  Neurol Psychiatry Brain Res. 2007;  14 ((2)) 45-50
• 23 Dyck PJ, Sherman WR, Hallcher LM. et al . Human diabetic endoneurial sorbitol, fructose and myo-inositol related to sural nerve morphometry.  Ann Neurol. 1980;  6 590-596
• 24 Jeffcoate W. Vascular calcification and osteolysis in diabetic neuropathy is RANK-L the missing link?.  Diabetologia. 2004;  47 1488-1492
• 25 Matthews DR, Hosker JP, Turner RC. Homeostasis Model Assesment: Insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 26 Bengman RN, Ider YZ, Bowden CR. et al . Quantitative estimation of insulin sensitivity.  Am J Physiol. 1979;  236 667-677
• 27 Mac Auley KA, Williams SM, Mann JI. et al . Diagnosing insulin resistance in the general population.  Diabetes Care. 2001;  24 460-464
• 28 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling.  Diabetes Care. 2004;  27 1487-1495
• 29 Katz A, Nambi SS, Mather K. et al . Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.  J Clin Endocrinol Metab. 2000;  85 2402-2410
• 30 Dyck PJ. Detection, characterization and staging of polyneuropathy: assessed in diabetics.  Muscle Nerve. 1998;  11 21-32
• 31 Jono S, Ikari Y, Shioi A. et al . Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease.  Circulation. 2002;  106 1192-1194
• 32 Dhore CR, Cleutjens JP, Lutgens E. et al . Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques.  Arterioscl Thromb Vas Biol. 2001;  21 1998-2003
• 33 Zhang J, Fu M, Myles D. et al . PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways.  FEBS Letters. 2002;  521 180-184
• 34 Malyankar UM, Scatena M, Suchland KL. et al . Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells.  J Biol Chem. 2000;  275 20959-20962

Correspondence