Osteopontin levels as a marker for diabetic vasculopathy in children and adolescents with type 1 diabetes mellitus

Abstract

SUMMARY D iabetes mellitus is a chronic metabolic disorder characterized by high plasma glucose caused by an impairment of insulin production, insulin action or both. Type 1 diabetes mellitus is potentially associated with serious microvascular and macrovascular complications. Diabetic nephropathy is a major cause of morbidity and mortality in patients with diabetes mellitus. Multiple markers of renal dysfunction, either tubular or glomerular, can appear before the detection of microalbuminuria, suggesting that microalbuminuria occurs once significant kidney damage has already occurred. Osteopontin has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling and inflammation. As an extracellular matrix protein and proinflammatory cytokine, osteopontin is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by osteopontin has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance. In view of these data, we measured the levels of osteopontin in young patients with type 1 diabetes and assessed its relation to inflammation, glycemic control and micro-vascular complications as well as carotid and aortic intima media thickness being non-invasive and sensitive index for the assessment of atherosclerosis. This cross sectional study was carried out on 60 children and adolescents with type 1 diabetes mellitus (27 males and 33 females with a male-to-female ratio 1:1.2) attending the Pediatric Diabetes Clinic, Pediatric Hospital, Ain Shams University. Another group of 30 age- and sex-matched healthy individuals; 17 males and 13 females (ratio, 1.1:1) were enrolled as controls. The mean age of patients was 11.5 ± 3.5 years (range, 8-17 years) while that of controls was 10.7 ± 3.2 years (range, 7-16 years). All the included patients were subjected to: (i) detailed medical history with special emphasis on age at onset of diabetes, disease duration, insulin therapy and chronic diabetic complications (retinopathy, neuropathy, nephropathy, or cardiovascular ischemic events); (ii) thorough clinical examination laying stress on anthropometric measures, blood pressure, fundus examination and neurological assessment; (iii) Laboratory investigations including measurement of mean fasting blood glucose (FBG), routine liver and Kidney function tests, fasting lipid profile, mean HbA1c%, urinary albumin excretion and high sensitivity C-reactive protein (hs-CRP). Determination of serum osteopontin levels by enzyme linked immunosorbent assay (ELISA); (iiii) Radiological investigations included carotid intima media thickness (CIMT) and aortic intima media thickness (AIMT). In the current work, it was observed that 18 patients out of 60 had nephropathy, 14 patients had peripheral neuropathy and 8 patients had retinopathy. Thus, the most common microvascular complication encountered in the studied patients was diabetic nephropathy being in 30% of patients. None of the studied patients had macro-albuminuria. Upon comparison of the clinical data between type 1 diabetic patients and control subjects, no significant difference was found as regards age, sex, weight SDS, height SDS and BMI between both groups. However, type 1 diabetic patients had significantly higher mean systolic and diastolic blood pressure, although values lie within normal range and none of the studied patients were hypertensive. Comparison between patients with and without micro-vascular complications revealed significantly higher FBG, HbA1c, serum creatinine, total cholesterol, UACR and hs-CRP among patients with micro-vascular complications than those without. CIMT and AIMT were significantly higher among patients compared with healthy controls. Moreover, CIMT and AIMT were significantly increased in patients with and without micro-vascular complications compared with healthy controls and the highest values were found among those with complications. As regards correlations between carotid or aortic IMT and clinical as well as laboratory variables, significant positive correlations were found between both CIMT and AIMT and each of FBG, HbA1c, serum creatinine and hs-CRP. Both carotid and aortic IMT were positively correlated. Osteopontin levels were significantly elevated in all diabetic patients compared with controls. Osteopontin was also significantly higher in patients with complications than patients without micro-vascular complications but levels were comparable among those without complications and controls. High osteopontin levels were found among patients with nephropathy or peripheral neuropathy compared with those without these complications. ROC curve analysis revealed that the cutoff value of Osteopontin at 90 ng/mL could differentiate patients with and without micro-vascular complications with a sensitivity of 71.7%, specificity of 95.8%. Significant positive correlations were observed between osteopontin and each of disease duration, FBG, HbA1c, UACR, CIMT and AIMT. Multiple regression linear analysis showed that FBG, HbA1c, UACR, CIMT and AIMT were independently related to osteopontin levels in type 1 diabetic patients. Logistic regression analysis showed that FBG, HbA1c, UACR, hs-CRP, osteopontin as well as carotid and aortic IMT are independently related to the presence of microvascular complications among type 1 diabetic patients. The diverse biological actions of (OPN) could potentially regulate many processes pertinent to vascular disease, including inflammation, cell adhesion, viability, angiogenesis, and calcification (Denhardt et al., 2001 and Abedin et al., 2004) Such actions may underlie its presumed role in the pathophysiology of atherosclerosis and in modulating arteriopathy associated with diabetes and chronic renal failure (Johnson et al., 2007).