Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study

Abstract

BackgroundType 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.MethodsThis study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45dimCD34+VEGFR-2+ and CD45dimCD133−CD34+CD144+ respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill’s colonies).ResultsAt baseline TG had lower cEPCs, PACs, CFU-Hills’ colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill’s colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill’s colonies with cECs.ConclusionsMetformin has potential cardio-protective effect through improving cEPCs, CFU-Hill’s colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long term cardiovascular outcome studies in type 1 diabetes.Trial registration ISRCTN26092132Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0413-6) contains supplementary material, which is available to authorized users.

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“…Moreover, we previously reported that the indices of vascular health, i.e., cEPC/CD45 dim CD34 + CD133 + cells, PACs, and fibronectin adhesion assay (FAA), were lower in T1DM patients versus HC [ 4 ].…”

“…otherwise known as circulating early endothelial progenitor cells (EPCs). It is well established, including by us, that in both type 1 and type 2 diabetic patients, there are fewer circulating EPCs than in HCs, confirming increased CVD risk [ 4 , 32 ]. EPCs have been proven to promote vascular repair via transmigration to promote new vessel growth and predict future CVD events [ 6 , 33 ].…”

“…We have previously published evidence to suggest that T1DM has features of early CVD without documented or apparent CVD events [ 3 , 4 , 5 ]. Patients with T1DM were characterized by a significant endothelial dysfunction, inflammatory state, reduced circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and colony forming units (Hills).…”

Metformin, lipids and atherosclerosis prevention

“…In a single paediatric centre experienced in FMD-and GTN-mediated vascular reactivity [32], with clinical confirmation of the latter in the T1D MERIT study [33].…”

Endothelial progenitor cell dysfunction in diabetes mellitus: new target for risk stratification and therapies?

“…However, impaired colony shaping, differentiation and migration abilities and survival in EPCs were dominated in diabetes across its nature evolution [17]. Indeed, hyperglycemia, insulin resistance and dyslipidemia are main triggers of putative EPC dysregulation by affecting the SDF-1/CXCR-4 and NO pathways and the p53/SIRT1/p66Shc axis that contribute to EPCs mobbing, migration, homing, differentiation and angiopoetic properties [18,19]. As a result altered balance between vascular injury and vascular reparation induces atherosclerosis, microvascular inflammation, pro-thrombotic state and thereby modulates target organ damages including retinopathy, renal disorders, cardiac failure, and peripheral artery disease [11].…”