Zinc supplementation improves glucose homeostasis in patients with ß-thalassemia major complicated with diabetes mellitus: A randomized controlled trial.

OBJECTIVES: The development of abnormal glucose tolerance in ß-thalassemia major (ß-TM) is associated with alterations in the oxidant-antioxidant status. Zinc is an antioxidant and an essential element for insulin synthesis, storage, and secretion. This randomized controlled trial assessed the effect of oral zinc supplementation on glucose homeostasis in pediatric ß-TM patients complicated with diabetes mellitus (DM). METHODS: Eighty patients were randomly assigned into two groups: an intervention group that received oral zinc in a dose of 40 mg/d for 12 wk and a placebo group. Hemolysis markers, serum ferritin, fasting blood glucose (FBG), fructosamine, fasting C-peptide, urinary albumin excretion (UAE), and serum zinc levels were assessed. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated. RESULTS: Baseline clinical and laboratory parameters were consistent among both groups. Baseline zinc levels were decreased in both groups compared with control values. After 12 wk, supplementation with zinc for the intervention group resulted in a significant decrease in lactate dehydrogenase, serum ferritin, FBG, fructosamine, HOMA-IR, and UAE, whereas fasting C-peptide was higher compared with baseline levels and with the placebo group (P < 0.05). Baseline serum zinc was negatively correlated to FBG (r = -0.534, P < 0.001) and fructosamine (r = -0.555, P < 0.001) but positively correlated to fasting C-peptide (r = 0.777, P = 0.002). CONCLUSIONS: Zinc supplementation as an adjuvant therapy in ß-TM patients with DM reduced iron burden, decreased hyperglycemia, increased insulin secretion, and improved glycemic control without any adverse effects.

Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Homocysteine levels are elevated in patients with type 1 diabetes mellitus (T1DM) and could induce renal injury. B vitamins have an important role in preventing microvascular complications of diabetes. AIM: We performed a randomized-controlled trial of oral supplementation with vitamin B complex as an adjuvant therapy for nephropathy in pediatric T1DM patients and assessed its relation to homocysteine and cystatin C as a marker of nephropathy. METHODS: This trial included 80 T1DM patients with microalbuminuria, despite oral angiotensin-converting enzyme inhibitors, aged 12-18 years with at least 5 years disease duration and HbA1c ≤8.5%. Patients were randomly assigned into two groups; intervention group which received oral vitamin B complex (B1, B6 and B12) once daily and placebo group. Both groups were followed-up for 12 weeks with assessment of plasma homocysteine, HbA1c, urinary albumin excretion (UAE) and cystatin C. RESULTS: Both groups were well-matched in baseline clinical and laboratory parameters. Baseline homocysteine levels were elevated in both groups compared with reference control values. After 12 weeks, supplementation with vitamin B complex for the intervention group resulted in a significant decrease of homocysteine, fasting blood glucose, HbA1c, triglycerides, total cholesterol, UAE and cystatin C compared with baseline levels (p < 0.001) and with placebo group (p < 0.001). No adverse reactions were reported. Baseline cystatin C was negatively correlated to vitamin B12 (r = -0.77, p = 0.001). CONCLUSIONS: Vitamin B complex improved glycemic control and renal function through decreasing homocysteine and could be a safe and effective strategy for treatment of early stage nephropathy in pediatric T1DM. This trial was registered at ClinicalTrials.gov (NCT03594240).

Renal iron deposition by magnetic resonance imaging in pediatric ß-thalassemia major patients: Relation to renal biomarkers, total body iron and chelation therapy.

BACKGROUND: The reciprocal of multiecho gradient-echo (ME-GRE) T2* magnetic resonance imaging (MRI) R2*, rises linearly with tissue iron concentration in both heart and liver. Little is known about renal iron deposition in ß-thalassemia major (ß-TM). AIM: To assess renal iron overload by MRI and its relation to total body iron and renal function among 50 pediatric patients with ß-TM. METHODS: Serum ferritin, serum cystatin C, urinary albumin creatinine ratio (UACR), and urinary ß2-microglobulin (ß2 M) were measured with calculation of ß2 M/albumin ratio. Quantification of liver, heart and kidney iron overload was done by MRI. RESULTS: Serum cystatin C, UACR and urinary ß2 microglobulin as well as urinary ß2m/albumin were significantly higher in ß-TM patients than the control group. No significant difference was found as regards renal R2* between Patients with mean serum ferritin above 2500 µg/L and those with lower serum cutoff. Renal R2* was higher in patients with poor compliance to chelation therapy and positively correlated to indirect bilirubin, LDH, cystatin C and LIC but inversely correlated to cardiac T2*. CONCLUSION: kidney iron deposition impairs renal glomerular and tubular functions in pediatric patients with ß-TM and is related to hemolysis, total body iron overload and poor compliance to chelation.

Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P < 0.001). Patients with hematuria or severe hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

Platelets microparticles as a link between micro- and macro-angiopathy in young patients with type 1 diabetes.

The development of vasculopathies in diabetes involves multifactorial processes. Increased levels of platelets-derived microparticles (PMPs) have been reported in diseases associated with thrombotic risk, but few data are available in diabetes. We explored the level of PMPs in young patients with type 1 diabetes in relation to inflammation, glycemic control, micro-vascular complications and carotid intima media thickness (CIMT). Eighty children and adolescents with type 1 diabetes were divided into two groups according to the presence of micro-vascular complications and compared with 40 healthy controls. Patients were subjected to medical history, clinical examination and assessment of high-sensitivity C-reactive protein (hs-CRP), HbA1c, urinary albumin creatinine ratio (UACR), flow cytometric analysis for PMPs using anti-CD41b and CIMT. PMP levels were significantly increased in all patients with type 1 diabetes (2.92 ± 1.3%) whether with micro-vascular complications (3.46 ± 1.11%) or those without complications (2.37 ± 1.28%) compared with healthy controls (1.28 ± 0.64%; p < 0.001). CIMT was significantly elevated in all patients, and the highest levels were among those with micro-vascular complications (p < 0.001). Significant positive correlations were found between PMPs and body mass index, HbA1c, serum creatinine, total cholesterol, UACR, hs-CRP and CIMT (p < 0.05). Multiple linear regression analysis showed that HbA1c, UACR, hs-CRP and CIMT were independently related to PMPs levels in type 1 diabetes. According to Receiver operating characteristic curve analysis, the cutoff value of PMPs at 2.48% could differentiate patients with and without micro-vascular complications with a sensitivity of 80% and specificity of 73.3%. PMPs are elevated in patients with type 1 diabetes and can be considered as an early marker of micro-vascular complications and subclinical atherosclerosis.

Growth differentiation factor-15 in young sickle cell disease patients: relation to hemolysis, iron overload and vascular complications.

BACKGROUND: High expression of growth differentiation factor-15 (GDF-15) contributes to pathological iron overload in thalassemia. Sickle cell syndromes are characterized by increased levels of erythropoiesis, although the primary defect involves the destruction of mature erythrocytes. AIM: To determine serum GDF-15 in 35 children and adolescents with sickle cell disease (SCD) compared to 35 healthy controls and assess its relation to markers of hemolysis, iron overload and vascular complications. METHODS: GDF-15 was measured and correlated to genotype, frequency of sickling crises, hydroxyurea therapy and serum ferritin. RESULTS: GDF-15 levels were increased in SCD patients whether sickle cell anemia or sickle ß° thalassemia compared with controls (p<0.001) with no significant difference between patients' groups. GDF-15 was significantly higher in patients who had serum ferritin ≥2500 µg/L, previous cerebral stroke, and splenectomy. GDF-15 was not significantly related to frequency of sickling crises, pulmonary hypertension, or hydroxyurea therapy. On regression analysis, transfusion index, lactate dehydrogenase and serum ferritin were independently related to GDF-15. CONCLUSION: Increased GDF-15 in SCD reflects the importance of ineffective erythropoiesis in the pathophysiology and severity of anemia in SCD. GDF-15 levels are related to hemolysis and iron overload and may provide utility for identifying patients at increased risk of thrombotic events.

Platelet function profile post-clopidogrel therapy in patients with type 2 diabetes undergoing coronary stent implantation.

Platelet dysfunction contributes to the increased risk of thromboischemic complications after percutaneous coronary intervention (PCI), particularly in type 2 diabetes. Little is known about the effects of glycemic control on platelet reactivity. We assessed adenosine diphosphate-induced platelet aggregation and flow cytometric expression of P-selectin in 90 patients (56 diabetic and 34 nondiabetic patients) undergoing coronary stent implantation after administration of clopidogrel as a potential predictor of poststent complications and its relation to glycemic control. Posttreatment platelet reactivity was significantly elevated in diabetic compared with nondiabetic participants and was associated with smoking, hypercholesterolemia, overweight, and cardiovascular ischemic events. A linear relationship was found between hemoglobin A1c in diabetic patients and platelet reactivity. Both methods (standard aggregometry and P-selectin expression) used for assessment of platelet function were positively correlated. Low responsiveness to clopidogrel detected by posttreatment platelet reactivity is a risk factor for ischemic events after PCI in diabetic patients.