Effect of Metformin on Circulating Neuregulin-4 in Children with Type 1 Diabetes

Abstract

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.