Mitigating iftar-related glycemic excursions in adolescents and young adults with type 1 diabetes on MiniMed™ 780G advanced hybrid closed loop system: a randomized clinical trial for adjunctive oral vildagliptin therapy during Ramadan fasting.

BACKGROUND: Ramadan Iftar meal typically causes glucose excursions. Dipeptidyl peptidase-4 inhibitors increase glucagon-like peptide-1 and thus, decrease blood glucose levels with low risk of hypoglycemia. AIM: To investigate the efficacy and safety of vildagliptin as an add-on therapy on glucose excursions of Iftar Ramadan meals among adolescents and young adults with type 1 diabetes mellitus (T1DM) using advanced hybrid closed-loop (AHCL) treatment. METHODS: Fifty T1DM patients on MiniMed™ 780G AHCL were randomly assigned either to receive vildagliptin (50 mg tablet) with iftar meal during Ramadan month or not. All participants received pre-meal insulin bolus based on insulin-to-carbohydrate ratio (ICR) for each meal constitution. RESULTS: Vildagliptin offered blunting of post-meal glucose surges (mean difference - 30.3 mg/dL [- 1.7 mmol/L] versus - 2.9 mg/dL [- 0.2 mmol/L] in control group; p < 0.001) together with concomitant exceptional euglycemia with time in range (TIR) significantly increased at end of Ramadan in intervention group from 77.8 ± 9.6% to 84.7 ± 8.3% (p = 0.016) and time above range (180-250 mg/dL) decreased from 13.6 ± 5.1% to 9.7 ± 3.6% (p = 0.003) without increasing hypoglycemia. A significant reduction was observed in automated daily correction boluses and total bolus dose by 23.9% and 16.3% (p = 0.015 and p < 0.023, respectively) with less aggressive ICR settings within intervention group at end of Ramadan. Coefficient of variation was improved from 37.0 ± 9.4% to 31.8 ± 7.1%; p = 0.035). No severe hypoglycemia or diabetic ketoacidosis were reported. CONCLUSION: Adjunctive vildagliptin treatment mitigated postprandial hyperglycemia compared with pre-meal bolus alone. Vildagliptin significantly increased TIR while reducing glycemic variability without compromising safety. Trial registration This trial was registered under ClinicalTrials.gov Identifier no. NCT06021119.

Omega-3 fatty acids supplementation improves early-stage diabetic nephropathy and subclinical atherosclerosis in pediatric patients with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Numerous studies have evaluated the beneficial effects of omega-3 fatty acids on inflammatory, autoimmune and renal diseases. However, data about the effects of omega-3 fatty acids on diabetic kidney disease in type 1 diabetes mellitus (T1DM) are lacking. OBJECTIVES: This randomized-controlled trial assessed the effect of oral omega-3 supplementation on glycemic control, lipid profile, albuminuria level, kidney injury molecule-1 (KIM-1) and carotid intima media thickness (CIMT) in pediatric patients with T1DM and diabetic nephropathy. METHODS: Seventy T1DM patients and diabetic nephropathy were enrolled with a mean age 15.2 ± 1.96 years and median disease duration 7 years. Patients were randomly assigned into two groups; intervention group which received oral omega-3 fatty acids capsules (1 g daily). The other group received a matching placebo and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c, fasting lipids, urinary albumin creatinine ratio (UACR), KIM-1 and CIMT. RESULTS: After 6 months, omega-3 fatty acids adjuvant therapy for the intervention group resulted in a significant decrease in FBG, HbA1c, triglycerides, total cholesterol, LDL-cholesterol, UACR, KIM-1 and CIMT, whereas, HDL-cholesterol was significantly higher post-therapy compared with baseline levels and compared with the control group (p < 0.05). Baseline KIM-1 levels were positively correlated to HbA1c, UACR and CIMT. Supplementation with omega-3 fatty acids was safe and well-tolerated. CONCLUSIONS: Omega-3 fatty acids as an adjuvant therapy in pediatric T1DM patients with diabetic nephropathy improved glycemic control, dyslipidemia and delayed disease progression and subclinical atherosclerosis among those patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT05980026.

MiniMed 780G™ advanced hybrid closed-loop system performance in Egyptian patients with type 1 diabetes across different age groups: evidence from real-world users.

BACKGROUND: Advanced hybrid closed loop (AHCL) system provides both automated basal rate and correction boluses to keep glycemic values in a target range. OBJECTIVES: To evaluate the real-world performance of the MiniMed™ 780G system among different age groups of Egyptian patients with type 1diabetes. METHODS: One-hundred seven AHCL system users aged from 3 to 71 years were enrolled. Data uploaded by patients were aggregated and analyzed. The mean glucose management indicator (GMI), percentage of time spent within glycemic ranges (TIR), time below range (TBR) and time above range (TAR) were determined. RESULTS: Six months after initiating Auto Mode, patients spent a mean of 85.31 ± 22.04% of the time in Auto Mode (SmartGuard) and achieved a mean GMI of 6.95 ± 0.58% compared with 7.9 ± 2.1% before AHCL initiation (p < 0.001). TIR 70-180 mg/dL was increased post-AHCL initiation from 63.48 ± 10.14% to 81.54 ± 8.43% (p < 0.001) while TAR 180-250 mg/dL, TAR > 250 mg/dL, TBR < 70 mg/dL and TBR < 54 mg/dL were significantly decreased (p < 0.001). After initiating AHCL, TIR was greater in children and adults compared with adolescents (82.29 ± 7.22% and 83.86 ± 9.24% versus 78.4 ± 7.34%, respectively; p < 0.05). The total daily dose of insulin was increased in all age groups primarily due to increased system-initiated insulin delivery including auto correction boluses and basal insulin. CONCLUSIONS: MiniMed™ 780G system users across different age groups achieved international consensus-recommended glycemic control with no serious adverse effects even in challenging age group as children and adolescents.

Fatty acid binding protein 1 (FABP1) and fatty acid binding protein 2 (FABP2) as a link between diabetic nephropathy and subclinical atherosclerosis in children and adolescents with type 1 diabetes.

BACKGROUND: Diabetic nephropathy is a major cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). Fatty acid binding proteins (FABP1 and FABP2) play a role in the development and progression of chronic kidney disease including type 2 diabetes mellitus. AIM: We assessed serum FABP1 and FABP2 levels in children and adolescents with T1DM as potential markers for diabetic nephropathy and their relation to carotid intima media thickness (CIMT). METHODS: Sixty patients with T1DM were divided into 2 groups according to the presence of nephropathy and compared with 30 healthy controls. CIMT, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), urinary albumin creatinine ratio (UACR), fasting lipid profile and serum FABP1 and FABP2 levels were assessed. RESULTS: FABP1 and FABP2 levels were significantly higher among type 1 diabetic patient with and without nephropathy compared with healthy controls with the highest levels among patients with nephropathy (p < 0.001). There were significant positive correlations between FABP1 and FABP2 and each of systolic blood pressure, CIMT, FBG, HbA1c and total cholesterol among T1DM patients. FABP1 was negatively correlated to glomerular filtration rate. Multivariable linear regression analysis showed that systolic blood pressure, CIMT, FBG and HbA1c were the significant independent variables related to FABP1 levels in type 1 diabetic patients with nephropathy. ROC curve analysis was performed to determine the cutoff value of FABP1 and FABP2 that could detect nephropathy. CONCLUSION: FABP1 and FABP2 levels are elevated in children and adolescents with T1DM and could represent a link between diabetic nephropathy and subclinical atherosclerosis.

Evaluation of the effect of eltrombopag therapy on the platelet collagen receptor glycoprotein VI (GPVI) expression and soluble GPVI levels in young patients with immune thrombocytopenia.

BACKGROUND: Platelet glycoprotein VI (GPVI) receptor is essential for platelet adhesion and aggregation. Eltrombopag is as an effective treatment for chronic immune thrombocytopenia (ITP); yet, its effect on platelet function is not fully characterized. AIM: This prospective study investigated the effect of eltrombopag therapy on platelet function through assessment of GPVI receptor expression and soluble GPVI levels among pediatric patients with persistent or chronic ITP. METHODS: Thirty-six children and adolescents with persistent or chronic ITP were divided equally into two groups either to receive eltrombopag therapy or the standard of care. All patients were followed-up for 12 months with assessment of bleeding score and complete blood count (CBC). Evaluation of GPVI expression using flow cytometry and measurement of its soluble form by ELISA was done at baseline and at 6 months. RESULTS: ITP patients on eltrombopag had significantly lower bleeding score after 6 months of therapy while the quality of life has significantly improved. Platelet count was significantly increased throughout the study. GPVI expression by flow cytometry and soluble GPVI levels were significantly increased after eltrombopag therapy. After 12 months, ITP patients on eltrombopag were able to maintain a good quality of life and low bleeding score. CONCLUSION: Our data suggest that eltrombopag, through its effect on the GPVI receptor expression and its soluble form, might reduce bleeding manifestations and improve the quality of life of chronic and persistent ITP children independent of its effect on the platelet count.

Endothelin-1 gene polymorphism (G8002A) and endothelial monocyte-activating polypeptide II: Role in vascular dysfunction in pediatric patients with ß-thalassemia major.

BACKGROUND: Endothelin-1 (ET-1), a potent endogenous vasoconstrictor, stimulates production of reactive oxygen species. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide. AIM: To assess ET-1 gene polymorphism (G8002A) in pediatric patients with ß-thalassemia major (ß-TM) as a potential genetic marker for vascular dysfunction and its possible relation to EMAP II, oxidative stress and vascular complications. METHODS: ß-TM patients (n = 95) without symptomatic cardiac or renal disease were compared with 95 healthy controls. Markers of hemolysis, serum ferritin, urinary albumin-to-creatinine ratio, serum EMAP II, malondialdehyde (MDA) and antioxidant enzymes; superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase and catalase were measured. ET-1 gene polymorphism (G8002A) was determined using polymerase chain reaction­restriction fragment length polymorphism. RESULTS: ß-TM patients had significantly higher EMAP II than healthy controls. EMAP II was significantly higher among patients with cardiac disease, pulmonary hypertension (PH) risk, nephropathy, poor compliance to therapy and ferritin ≥ 2500 µg/L. There were significant correlations between EMAP II and transfusion index, LDH, ferritin and oxidative stress markers. The AA genotype of ET-1 gene polymorphism (G8002A) was significantly higher among ß-TM patients than controls. The number of patients with cardiac disease, PH risk or nephropathy was significantly higher among AA genotype compared with GG and GA genotypes. Lactate dehydrogenase (LDH), serum ferritin, EMAP II, MDA, SOD and GPx were significantly higher in AA genotype. CONCLUSION: ET-1 gene polymorphism (G8002A) could be a possible genetic marker for prediction of increased susceptibility to cardiopulmonary and renal complications among pediatric patients with ß-TM.

Glycemic control during Ramadan fasting in adolescents and young adults with type 1 diabetes on MiniMed™ 780G advanced hybrid closed­loop system: A randomized controlled trial.

BACKGROUND: MiniMedTM 780G is the most advanced insulin pump system approved for the treatment of type 1 diabetes mellitus (T1DM). Hypoglycemic events are a serious complication associated with T1DM management during Ramadan fasting. AIM: This prospective study assessed the safety, effectiveness and optimization of advanced hybrid closed loop (AHCL) system on glycemic metrics and the level of hypoglycemia in T1DM patients who wished to fast Ramadan. METHODS: Forty-two T1DM patients (mean age 15.2 ± 3.4 years) using AHCL system were divided into two groups (each n = 21): intervention group who adjusted AHCL settings and control group who kept the same settings as before Ramadan. RESULTS: The most aggressive system settings among control group consisting of a 100 mg/dL glucose target, active insulin time of 2 h and bolus increment,maintained exceptional glycemia withtime in range reaching82.0 ± 10.2%, time above range >180 mg/dL of 12.1 ± 3.5% without an increase in hypoglycemia (time below range 3.0 ± 0.3%). All of which were non-significant in comparison to the intervention group. Overall time spent in closed loop (SmartGuard) by users averaged 98.7 ± 2.1% in Auto Mode and involved only 1.0 ± 0.7 exits per week indicating confidence in the system's performance. There were no severe hypoglycemic or diabetic ketoacidosis events during the study. CONCLUSIONS: MiniMed™ 780G AHCL system assist in safe fasting with minimal user input and allows for achievement of recommended glycemic targets in people with T1DM during Ramadan fasting. The system demonstrated reduction in hypoglycemia exposure without compromising safety.

Effect of metformin as an add-on therapy on neuregulin-4 levels and vascular-related complications in adolescents with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Inflammation is closely associated with atherosclerosis and plays a crucial role in the development of cardiovascular disease. Metformin sensitizes body cells to insulin, which may cause a reduction of atherogenic lipid fractions. Low neuregulin-4 (Nrg-4) levels, an adipokine, are linked to obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes. OBJECTIVES: We assessed the effect of oral supplementation with metformin on glycemic control, neuregulin-4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in adolescents with type 1 diabetes mellitus (T1DM) and microvascular complications. METHODS: This randomized placebo-controlled trial included 80 type 1 diabetic patients with microvascular complications who were randomly divided to receive either 24 weeks of metformin 500 mg/day or matching placebo. Fasting blood glucose (FBG), HbA1c, C-reactive protein (CRP), urinary albumin creatinine ratio (UACR), lipid profile, Nrg-4 and CIMT were assessed at baseline and study end. RESULTS: Both groups were well-matched as regards baseline clinical and laboratory data (p greater than 0.05). After 24-weeks, metformin therapy for the intervention group resulted in a significant decrease of HbA1c, CRP, UACR, total cholesterol and CIMT while Nrg-4 levels were increased compared with baseline levels (p < 0.001) and with placebo group(p < 0.001). Baseline Nrg-4 levels were negatively correlated to FBG, HbA1c, total cholesterol, CRP and CIMT. Metformin was well-tolerated. CONCLUSIONS: Oral metformin supplementation once daily for 24 weeks as an adjuvant therapy to intensive insulin in pediatric T1DM was safe and effective in improving glycemic control, dyslipidemia and Nrg-4 levels; hence, it decreased inflammation, microvascular complications and subclinical atherosclerosis.

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).

Serum visfatin level as a noninvasive marker for nonalcoholic fatty liver disease in children and adolescents with obesity: relation to transient elastography with controlled attenuation parameter.

BACKGROUND: Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Visfatin is an adipokine produced by visceral fat tissue and liver cells. Transient elastography with controlled attenuation parameter (CAP) noninvasively assesses liver fibrosis and steatosis. AIM: To measure visfatin level in 80 children and adolescents with obesity as a potential biomarker for NAFLD and assess its relation to transient elastography. METHODS: Abdominal ultrasound, liver stiffness and CAP measurements were performed for all patients. Fasting lipid profile, fasting blood glucose, insulin level, liver and kidney functions, coagulation profile and serum visfatin levels were assessed. RESULTS: Among patients with obesity, 31 (38.8%) had NAFLD and 16 (20%) patients had elevated alanine aminotransferase (ALT), while 9 (11.2%) had both NAFLD and elevated ALT. Transient elastography showed that 12.5% had fibrosis stage F1, 2.5% had F2 and another 2.5% had F3 while none had F4. Using CAP, 23.8, 13.8 and 17.5% had S1, S2 and S3, respectively. Serum visfatin levels were significantly elevated in all patients compared with nonobese controls. Higher visfatin levels were found among patients with dyslipidemia, NAFLD, elevated ALT and steatosis defined by CAP. Serum visfatin was related to the degree of fibrosis and steatosis. Visfatin cutoff value 18 ng/mL could significantly detect the presence of NAFLD with 83.9% sensitivity and 81.4% specificity. Serum visfatin was positively correlated to BMI, waist circumference, waist/hip ratio, ALT, total cholesterol, liver stiffness and CAP. CONCLUSIONS: Visfatin could be a promising serum biomarker for monitoring liver disease among pediatric patients with obesity.

Angiotensinogen M235T Gene Polymorphism is a Genetic Determinant of Cerebrovascular and Cardiopulmonary Morbidity in Adolescents with Sickle Cell Disease.

BACKGROUND: Cerebrovascular stroke is a common critical complication of sickle cell disease (SCD). Angiotensinogen (AGT) M235T gene polymorphism is associated with risk of ischemic stroke and cardiovascular disease. AIM: We investigated the potential association between angiotensinogen M235T gene polymorphism and susceptibility to cerebrovascular and cardiopulmonary complications in adolescents with SCD. METHODS: Forty-six patients with SCD in steady state were studied stressing on history of stroke, hydroxyurea/chelation therapy, hematological profile, and echocardiographic findings. Polymerase chain reaction-based restriction fragment length polymorphism analysis was used to detect AGT M235T gene polymorphism. Fifty sex- and age-matched healthy controls were enrolled for assessment of M235T gene polymorphism pattern. RESULTS: The distribution of AGT M235T gene polymorphism was similar between SCD patients and healthy controls. The frequency of T allele of AGT M235T gene polymorphism (TT and MT genotypes) was significantly higher among patients with history of manifest stroke (P < .001). Patients with TT and MT genotypes had higher incidence of cardiopulmonary complications (P = .041) as well as higher percentage of HbS (P < .001) and lower hemoglobin level (P = .008) compared with those with MM genotype. Serum ferritin, liver iron concentration, and cardiac T2* were not related to T alleles or genotypes. Logistic regression analysis revealed that M235T genotype was a significant independent factor related to the occurrence of stroke among patients with SCD (Odds Ratio 14.05, 95% confidence interval 3.82-28.91; P = .001). CONCLUSION: AGT M235T gene polymorphism may represent a genetic modifier to vascular morbidities in Egyptian patients with SCD.

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy.

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4+CD28null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4+CD28null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4+CD28null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4+CD28null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4+CD28null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4+CD28null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4+CD28null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

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.

Osteopontin as a marker of vasculopathy in pediatric patients with type 1 diabetes mellitus: Relation to vascular structure.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is associated with serious micro-vascular and macro-vascular complications. Osteopontin (OPN) has emerged as a strong predictor of incipient diabetic nephropathy and a first-ever cardiovascular event in adults with T1DM. OPN is linked to coronary atherosclerosis in type 2 diabetes. The aim of the study was to test the hypothesis that OPN could be a potential marker for micro-vascular complications in children and adolescents with T1DM and we assessed its relation to carotid and aortic intima media thickness (CIMT and AIMT) as non-invasive index for subclinical atherosclerosis. METHODS: Eighty patients with T1DM ≤18 years were divided into 2 groups according to the presence of micro-vascular complications and compared with 40 age- and sex-matched healthy controls. Fasting blood glucose, high sensitivity C-reactive protein (hs-CRP), HbA1c, urinary albumin creatinine ratio (UACR), OPN, CIMT, and AIMT were assessed. RESULTS: Both CIMT and AIMT were significantly higher in patients with and without micro-vascular complications compared with healthy controls (P < .001). OPN concentrations were significantly elevated in all diabetic patients compared with controls (P = .002). OPN was also significantly higher in patients with micro-vascular complications than patients without (P < .001) but levels were comparable among those without complications and controls (P = .322). Receiver operating characteristic curve analysis revealed that OPN cut-off value 90 ng/mL could differentiate patients with and without micro-vascular complications with 81.7% sensitivity and 95.8% specificity. Significant positive correlations were found between OPN and HbA1c, UACR, CIMT, and AIMT. CONCLUSIONS: OPN could be considered a marker of vasculopathy and subclinical atherosclerosis in pediatric T1DM.

Role of neopterin as a biochemical marker for peripheral neuropathy in pediatric patients with type 1 diabetes: Relation to nerve conduction studies.

BACKGROUND: Neopterin, a marker of inflammation and cellular immune response, is elevated in conditions of T-cell or macrophages activation. Diabetic peripheral neuropathy (DPN) is associated with inflammatory/immune processes and therefore, we hypothesized that neopterin could be used as a marker of neuropathy in type 1 diabetes mellitus (T1DM). AIM: To measure neopterin levels in children and adolescents with T1DM and assess its possible relation to DPN and nerve conduction studies (NCS). METHODS: Sixty patients aged ≤18 years and >5 years disease duration were subjected to neurological assessment by neuropathy disability score (NDS) and NCS for median, ulnar, posterior tibial and common peroneal nerves. Mean fasting blood glucose, lipid profile, HbA1c, high sensitivity C-reactive protein (hs-CRP) and serum neopterin levels were assessed. Patients were compared with 30 age- and sex-matched healthy controls. RESULTS: The frequency of DPN according to NDS was 40 (66.7%) patients out of 60 while NCS confirmed that only 30 of those 40 patients had this complication (i.e. 50% out of the total studied patients). Neopterin levels were significantly higher in patients with DPN than those without (median [IQR], 53.5 [35-60] nmol/L versus 17 [13-32] nmol/L) and healthy controls (5.0 [3.2-7.0] nmol/L) (p < 0.001). Significant positive correlations were found between neopterin levels and HbA1c (r = 0.560, p = 0.005), serum creatinine (r = 0.376, p = 0.003), total cholesterol (r = 0.405, p = 0.026) and hs-CRP (r = 0.425, p = 0.012) among patients with DPN. Neopterin levels were positively correlated to motor latency of tibial and common peroneal nerves as well as motor and sensory latencies of median and ulnar nerves. Logistic regression analysis revealed that neopterin was a significant independent variable related to DPN (Odds ratio, 2.976). Neopterin cutoff value 32 nmol/L could differentiate patients with and without DPN with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Neopterin could be used as an early reliable serum biomarker for DPN in pediatric patients with T1DM.

The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo-controlled trial.

BACKGROUND AND OBJECTIVES: Oxidative stress is a significant contributor to the pathogenesis of diabetic nephropathy. Carnosine is a natural radical oxygen species scavenger. We investigated the effect of carnosine as an adjuvant therapy on urinary albumin excretion (UAE), the tubular damage marker alpha 1-microglobulin (A1M), and oxidative stress in pediatric patients with type 1 diabetes and nephropathy. METHODS: This randomized placebo-controlled trial included 90 patients with diabetic nephropathy, despite oral angiotensin-converting enzyme inhibitors (ACE-Is), who were randomly assigned to receive either 12 weeks of carnosine 1 g/day (n = 45), or matching placebo (n = 45). Both groups were followed-up with assessment of hemoglobin A1c (HbA1c), UAE, A1M, total antioxidant capacity (TAC) and malondialdhyde (MDA). RESULTS: Baseline clinical and laboratory parameters were consistent between carnosine and placebo groups (P > .05). After 12 weeks, carnosine treatment resulted in significant decrease of HbA1c (8.2 ± 2.1% vs 7.4 ± 1.3%), UAE (91.7 vs 38.5 mg/g creatinine), A1M (16.5 ± 6.8 mg/L vs 9.3 ± 6.6 mg/L), MDA levels (25.5 ± 8.1 vs 18.2 ± 7.7 nmol/mL) while TAC levels were increased compared with baseline levels (P < .001) and compared with placebo (P < .001). No adverse reactions due to carnosine supplementation were reported. Baseline TAC was inversely correlated to HbA1c (r = -0.58, P = .04) and A1M (r = -0.682, P = .015) among carnosine group. CONCLUSIONS: Oral supplementation with L-Carnosine for 12 weeks resulted in a significant improvement of oxidative stress, glycemic control and renal function. Thus, carnosine could be a safe and effective strategy for treatment of pediatric patients with diabetic nephropathy.

Soluble fms-Like Tyrosine Kinase 1 as a Link Between Angiogenesis and Endothelial Dysfunction in Pediatric Patients With ß-Thalassemia Intermedia.

Endothelial damage has been implicated in the pathogenesis of vascular complications in ß-thalassemia intermedia (ß-TI). Soluble fms-like tyrosine kinase 1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. Soluble fms-like tyrosine kinase 1 is an antiangiogenic protein that induces endothelial dysfunction by adhering to and inhibiting VEGF and placenta growth factor. The aim of this study was to assess the level of sFLT-1 in 35 children and adolescents with ß-TI, correlating it with markers of hemolysis and iron overload as well as cardiopulmonary complications. Patients were studied focusing on the history of cardiac disease, splenectomy, transfusion, chelation/hydroxyurea therapy, serum ferritin, and sFLT-1 levels. Echocardiography and measurement of carotid intima-media thickness (CIMT) were done for all participants. Soluble fms-like tyrosine kinase 1 was significantly higher in TI patients compared to the control group (median [interquartile range], 110 [80-155] pg/mL versus 70 [60-90] pg/mL; P < .001). Splenectomized patients and those who had pulmonary hypertension risk or heart disease had higher sFLT-1 levels than those without ( P < .001). The sFLT-1 cutoff value that differentiates patients with and without pulmonary hypertension risk or heart disease was determined. Soluble fms-like tyrosine kinase 1 was lower among patients who received chelation therapy and/or hydroxyurea. Significant positive relations were observed between sFLT-1 and lactate dehydrogenase, serum ferritin, liver iron concentration, tricuspid regurgitant jet velocity, and CIMT. We suggest that sFLT-1 represents a link between angiogenesis, endothelial dysfunction, and subclinical atherosclerosis. Measurement of sFLT-1 as a marker of vascular dysfunction in ß-TI may provide utility for early identification of patients at increased risk of cardiopulmonary complications.

Ischemia-modified albumin as a marker of vascular dysfunction and subclinical atherosclerosis in ß-thalassemia major.

BACKGROUND: Ischemia-modified albumin (IMA) is an altered type of serum albumin that forms under conditions of oxidative stress and an independent predictor of major adverse cardiovascular events. OBJECTIVES: To measure the levels of IMA in 45 children and adolescents with ß-thalassemia major (ß-TM) compared with 30 healthy controls and assess its relation to lipid peroxidation, vascular complications and subclinical atherosclerosis. METHODS: ß-TM patients without symptoms of heart disease were studied focusing on transfusion history, chelation therapy, serum ferritin, malondialdehyde (MDA) and IMA levels. Echocardiography was performed and carotid intima media thickness (CIMT) was assessed. RESULTS: IMA and MDA levels were significantly higher in ß-TM patients compared with controls (p < 0.001). IMA was higher among patients with heart disease, pulmonary hypertension risk and serum ferritin ≥2500 µg/l than those without. TM patients compliant to chelation had significantly lower IMA levels. IMA levels were positively correlated to MDA and CIMT while negatively correlated to ejection fraction and fractional shortening. CONCLUSION: Our results highlight the role of oxidative stress in the pathophysiology of vascular complications in thalassemia. IMA could be useful for screening of ß-TM patients at risk of cardiopulmonary complications and atherosclerosis because its alteration occurs in early subclinical disease.

Tartrate-Resistant Acid Phosphatase 5b in Young Patients With Sickle Cell Disease and Trait Siblings: Relation to Vasculopathy and Bone Mineral Density.

Bone involvement is a frequent cause of acute morbidity in sickle cell disease (SCD). Tartrate-resistant acid phosphatase 5b (TRACP 5b), a bone resorption marker, is produced specifically by activated osteoclasts. We assessed bone mineral density (BMD) in 30 young patients with SCD and 17 asymptomatic patients with sickle cell trait (SCT) compared with 32 healthy controls and determined TRACP 5b levels in relation to vascular complications. Serum ferritin, alkaline phosphatase (ALP), and TRACP 5b were measured. Echocardiography was performed with assessment of BMD using dual energy X-ray absorptiometry (DXA). The BMD was decreased in patients with SCD compared with SCT and controls (P = .005), with no significant difference between the latter 2 groups. Patients with SCD had higher incidence of bone complications than SCT group and controls (P = .03). The SCD group with abnormal DXA scan had higher ferritin and ALP than normal BMD. Serum TRACP 5b was significantly higher in patients with SCD than SCT and controls (P = .003). The TRACP 5b levels were associated with severe vaso-occlusive crisis (P = .022). Patients treated with hydroxyurea and those on chelation therapy had lower TRACP 5b levels than untreated patients. The TRACP 5b level was positively correlated with lactate dehydrogenase, while there was no relation with ferritin, ALP, or BMD. We suggest that bone complications frequently occur in SCD as reflected by low BMD and high ALP and TRACP 5b. Hemolysis and iron overload may be involved in the occurrence of these complications. The lack of correlation between abnormal DXA scan and high TRACP 5b suggests that bone disease in SCD is multifactorial.