Circulating Angiopoietin-2 in Young Patients with Type 1 Diabetes Mellitus

Abstract

SUMMARY 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. Angiopoietin-2 (Ang-2) is an important proangiogenic factor that has more recently been implicated in mediating inflammatory processes as well. Ang-2 is upregulated in multiple inflammatory diseases and has been implicated in the direct control of inflammation-related signaling pathways. As a consequence of its multiple roles, designs for therapeutic targeting of Ang-2 should consider the dual function of this factor in regulating angiogenesis and inflammation. Carotid or aortic scans provide non-invasive screening tools for assessment of preclinical atherosclerosis in high-risk children. In view of these data, we measured the levels of Angiopoietin-2 in children and adolesecnts 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) attending the Pediatric Diabetes Clinic, Pediatric Hospital, Ain Shams University. D Summary 187 Another group of 30 age- and sex-matched healthy individuals; 17 males and 13 females were enrolled as controls. The mean age of patients was 11.5 ± 3.5 years (range, 6-17 years) while that of controls was 10.7 ± 3.2 years (range, 5-16 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 Angiopoietin-2 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 20 patients out of 60 had nephropathy, 15 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 33.3% of patients. None of the studied patients had macro-albuminuria. Summary 188 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 microvascular 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. Angiopoietin-2 levels were significantly elevated in diabetic patients with and without microvascular complications compared with controls. High Angiopoietin-2 levels were found among patients with nephropathy or peripheral Summary 189 neuropathy compared with those without these complications. ROC curve analysis revealed that the cutoff value of Angiopoietin-2 at 900 pg/mL could differentiate patients with and without micro-vascular complications with a sensitivity of 92.3%, specificity of 100%. Significant positive correlations were observed between Angiopoietin-2 and each of FBG, HbA1c, serum creatinine, hs- CRP, CIMT and AIMT. Multiple regression linear analysis showed that FBG, HbA1c, hs-CRP, CIMT and AIMT were independently related to Angiopoietin-2 levels in type 1 diabetic patients. Logistic regression analysis showed that FBG, HbA1c, UACR, hs-CRP, angiopoietin-2 as well as CIMT and AIMT are independently related to the presence of microvascular complications among type 1 diabetic patients.