The impact of metformin on cardiovascular markers in type 1 diabetes :MERIT study

Abstract

Type 1 diabetes mellitus (T1DM) is characterised by an increased risk of cardiovascular disease (CVD). Metformin has been shown to have cardio-protective properties in type 2 diabetes. We aimed to determine if the cardio-protective effect of metformin is mediated by modulating circulatory biomarkers in T1DM whilst maintaining unchanged glycemic control. Twenty-three T1DM patients without overt CVD were treated with metformin for eight weeks (treatment group-TG). They were matched with nine T1DM patients on standard treatment (SG) and twenty-three age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control in TG. We evaluated endothelial progenitor cells (cEPCs-CD45dimCD34+VEGFR2+ ), circulatory endothelial cells (cECs-CD45dimCD133−CD34+CD144+ ), , microRNAs (miR), cytokines (all groups), microparticles (MP) and peripheral mononuclear cells (PBMC) (except SG). At baseline, TG had lower cEPCs, Pro-angiogenic cells (PACs), (Colony forming Unit) CFU-Hills’ colonies, and PACs adhesion and higher cECs, Endothelial-MPs(EMPAnnexinV+CD31+CD41- ) and Platelet-MPs (PMP-AnnexinV+CD31+CD41+ ) versus HC. Metformin improved cEPCs, PACs, CFU-Hills’ colonies, cECs number and PACs adhesion in TG to levels seen in HC whilst EMPs and PMPs levels did not change. miR-21, miR-222, miR-195, miR-210, miR-223 and miR-320 levels were higher in TG when compared to HC. In TG, miR-21, miR-222, miR-195 and miR-210 levels reduced significantly after metformin treatment. Inflammatory cytokines and tissue inhibitors of metalloproteinase-1 (TIMP-1) were higher in T1DM when compared to HC. Vascular injury markers were not raised in T1DM when compared to HC. After metformin treatment, TIMP-1, IL-6 and thrombomodulin levels reduced significantly. In TG, metformin treatment significantly modulated eleven genes in PBMC. These genes were involved in MAP signalling kinase pathway, inflammatory response, cell movement, death, signalling and survival. ii We have demonstrated that metformin can potentially shift the balance towards vascular repair. This can be mediated via improvement in EPC mobilisation, survival, inflammatory status and proangiogenic miRs. independent of metformin’s glucose lowering effect. However further long-term cardiovascular outcome studies in T1DM are still required.