Exploring Cardio-Metabolic Effects of Liraglutide in Patients With Type 2 Diabetes Through a Proteomic Approach

Background: Diabetes is associated with complications that increase the risk of cardiovascular events in diabetic patients by 3 folds compared to healthy population. Liraglutide is a GLP-1 receptors agonist that showed cardiovascular benefits beside its glycemic advantage and weight reduction. The cardioprotective benefit of liraglutide in diabetic patients is unclear. Objective: To explore potential cardiovascular-protective and metabolic effects of Liraglutide treatment in patients with T2DM, through evaluation of alterations in circulatory proteins using a proteomics approach. To relate the altered proteins to identify pathways using bioinformatics and network pathway analysis. Methods: Twenty adult patients with T2DM were recruited with HbA1c of 8–11 %, on oral anti-diabetic agents or insulin in whom liraglutide was indicated, after obtaining the consent. At baseline: anthropometric measurements, basal blood for HBA1c, Renal function, creatinine clearance, lipid profile and urine in the fasting state. Then Liraglutide 1.8 mg subcutaneous once daily injection was initiated as prescribed by the treating physician. AT 3 months follow up visit post-treatment, similar parameters were measured. Primary endpoint was the reduction from baseline in HbA1c for ≥ 0.5 %. Results: Alterations in the abundance of urinary proteins, analyzed by Progenesis software, revealed statistically significant differential abundance in a total of 80 spots corresponding to 71 proteins, 14 up and 57 down (≥1.5-fold change, ANOVA, p ≤ 0.05) in the post treatment group. The proteins identified in our study are known to regulate processes related to acute phase response (APR), cellular metabolism and transport. The post treatment group demonstrated an increased abundance of proteins that included alpha-1-antitrypsin, alpha-1-antichymotrypsin, serotransferrin, transthyretin, plasma protease C1 inhibitor, adenosylhomocysteinase 3 and beta-2-glycoprotein 1. The proteins with a decrease in abundance following treatment included transthyretin, serotransferrin, haptoglobin, complement C3, retinol binding protein and ceruloplasmin. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) identified dysregulation of pathways related cellular compromise, inflammatory response, and neurological disease. It also identified the involvement of the inflammatory signalling pathways, NFκb, AKT, p38 MAPK via their interactions with interleukin 12 as the central nodes. Conclusion: The altered proteins identified in the present study showed an increase in the APR in patients with diabetes before treatment with liraglutide which was significantly reduced in the post treatment group. Increase in the APR is known to lead to a state of chronic inflammation predisposing individuals to cardiometabolic stress and disease.