الفهرس 
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Abstract
T
he increasing incidence of type 1 diabetes mellitus in many countries challenges health systems because the disease is presently incurable with no known method of prevention. Many guidelines recommend metformin as first-line therapy for patients with type 2 diabetes. Metformin monotherapy tends to reduce mortality and cardiovascular morbidity and mortality. Some studies investigated the effects of metformin in patients with type 1 diabetes mellitus (T1DM) but no enough data on its effect on vascular health and microvascular complications in pediatric patients with T1DM.
Neuregulin-4 (Nrg4) is one of the four neuregulin family proteins: cell-cell signaling proteins that possess an EGF-like domain and bind to the ErbB family tyrosine kinase receptors. Overexpression of Nrg4 can reduce chronic inflammation through inhibiting the gene expression of macrophage marker monocyte chemotactic protein 1 (MCP1) and enhancing the expression of M2 macrophage marker gene CD163, demonstrating that Nrg4 may possess anti-inflammatory and anti-atherogenic properties. Lower Nrg4 levels have been reported to be associated with insulin resistance, impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM).
In view of these data, we assessed the effect of oral supplementation with metformin on glycemic control, lipid profile, Nrg4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in pediatric T1DM patients with micro-vascular complications.
This study was carried out on 80 children and adolescents with type 1 diabetes mellitus and microvascular complications (46 males and 34 females) attending the Pediatric Diabetes Clinic, Pediatric Hospital, Ain Shams University. Enrolled patients aged 12-18 years with disease duration > 5 years. The mean age of patients was 15.4 ± 1.7 years (range, 13-18 years). Thirty-nine patients had nephropathy (48.8%) and 41 patients had neuropathy (51.2%).
Each of the eligible children was randomly assigned by simple randomization to either group I and group II.
group I (Metformin group): consists of 40 pediatric patients having T1DM with microvascular complications. Patients received oral metformin tablets (GLUCOPHAGE® 500mg tablet manufactured by Minapharm Pharmaceuticals under licence of Merk santé, France (MERCK SERONO) in a dose of 1 tablet once daily after lunch. Each film coated tablet contains metformin hydrochloride 500mg (equivalent to metformin base 390mg). Their formulation consists of a white-colored and rounded-shaped tablet. Metformin was taken with meals to minimize gastrointestinal side effects. Starting dosage was 500 mg/day (at breakfast) for one week, and was increased by 500 mg/day to reach a maximum dose of 1000 mg/day (500 mg twice daily) for six months.
group II (Non-Metformin group): consists of 40 pediatric patients having T1DM with microvascular complications who did not receive oral metformin tablets.
All included patients were subjected to i) detailed medical history with special emphasis on disease duration and insulin therapy; ii) thorough clinical examination laying stress on assessment of body mass index, blood pressure (mmHg), complete examination including chest, heart, abdomen and neurological examination for evidence of any diabetic complications; iii) laboratory investigations including measurement of mean fasting blood glucose levels in the last 3 months prior to the study, routine liver and kidney function tests including serum creatinine, fasting lipid profile, assessment of mean HbA1c%, and high sensitivity C-reactive protein (hs-CRP). Estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault equation. Urinary albumin excretion (UAE) was measured in an early morning fasting urine sample as albumin-to-creatinine ratio (UACR) by an immune-turbidimetric method. Nrg-4 levels were assessed using ELISA. Carotid intima media thickness (CIMT) was assessed using high-resolution ultrasound. All patients were followed-up for 6 months.
Upon comparison between baseline clinical or laboratory data and CIMT among T1DM patients with and without metformin therapy, no significant difference was found.
Comparison between T1DM patients with metformin therapy at baseline and at 6-months post-therapy showed significantly lower weight, BMI, systolic BP, diastolic BP, FBG, RBG, HbA1c, triglycerides, total cholesterol and UACR. Moreover, Nrg-4 levels were markedly elevated while hs-CRP and CIMT was significantly decreased post-therapy compared with baseline levels. The recorded adverse reactions to oral metformin therapy throughout the 6 months of therapy were tolerable and in the form of gastrointestinal disturbances (nausea, heartburn, flatulence and diarrhea) in 5 patients.
As regards type 1 diabetic patients without metformin, they had significantly higher weight, BMI, systolic BP, RBG and CIMT while Nrg-4 levels were decreased at the end of the study compared with baseline levels while other variables were consistent
Comparison between type 1 diabetic patients with microvascular complication with and without metformin therapy at the end of the study revealed significantly lower BMI, systolic BP, FBG, RBG, HbA1c, total cholesterol, UACR, hs-CRP and CIMT levels while Nrg-4 levels were significantly increased in those who received metformin therapy compared with the other group.
Correlation studies revealed significant negative correlation between baseline Nrg-4 levels and each of diastolic blood pressure, FBG, RBG, HbA1c, total cholesterol, hs-CRP and CIMT. Multivariable linear regression analysis showed that baseline FBG, RBG, HbA1c, hs-CRP, and CIMT were the significant independent variables that affect Nrg-4 levels among type 1 diabetic patients with microvascular complications.