Anti-Angiogenic miR-222, miR-195, and miR-21a Plasma Levels in T1DM Are Improved by Metformin Therapy, Thus Elucidating Its Cardioprotective Effect: The MERIT Study

Abstract

Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, 23 T1DM patients without CVD were treated with metformin for eight weeks (TG), matched with nine T1DM patients on standard treatment (SG) and 23 controls (CG). Plasma miR-222, miR-195, miR-21a and miR-126 were assayed by real-time RT-qPCR. The results were correlated with: endothelial function (RHI), circulating endothelial progenitor cells (cEPCs) (vascular repair marker, CD45dimCD34+VEGFR2+ cells) and circulating endothelial cells (cECs) (vascular injury marker, CD45dimCD34+CD133-CD144+ cells). miR-222, miR-195 and miR-21a were higher in T1DM than CG; p = 0.009, p < 0.0001, p = 0.0001, respectively. There was an inverse correlation between logmiR-222 and logRHI (p < 0.05) and a direct correlation between logmiR-222 and logCD34+ (p < 0.05) in TG. Metformin reduced miR-222, miR-195 and miR-21a levels in TG; p = 0.007, p = 0.002 p = 0.0012, respectively. miRs remained unchanged in SG. miR-126 was similar in all groups. There was a positive association between changes in logmiR-222 and logcECs after metformin in TG (p < 0.05). Anti-angiogenic miRs are increased in T1DM. Metformin has cardioprotective effects through downregulating miR-222, miR-195 and miR-21a, beyond improving glycemic control.

MicroRNAs Modulation and Clinical Outcomes at 1 Year of Follow-Up After Excision of Subcutaneous Abdominal Fat in Overweight Patients with Pre-Diabetes Treated with Metformin vs. Placebo

“…Therefore, taken together our study results might evidence, in obese patients with pre-diabetes, the implication of miR-195 and miR-27 as regulators of glucose homeostasis and insulin resistance, and of inflammation/oxidative stress pathways which are implied in cardiovascular remodeling (17)(18)(19)(20)(21)(22)(23)(24)(25). Notably and clinically relevant, the metformin in these patients could modulate these metabolic and inflammatory pathways, leading to cardio-protective effects.…”

“…In addition, in diabetic mice model the knockdown of miR-195 increased myocardial capillary density and improved maximal coronary blood flow, leading to the reduction of diabetic cardiomiopathy (20). Therefore, metformin therapy could cause down regulation of miR-195, beyond improving glycemic control and insulin resistance, and leading to cardio-protective effects (21). Similarly, the expression of miR-27 is increased in fat tissue of obese mice, and in patients with metabolic syndrome and type 2 diabetes mellitus (23).…”

“…Furthermore, miR-195 and miR-27 could become targets for the treatment of obesity and insulin resistance, and to revert the pathological shifting from over inflammation/oxidative stress to cellular hyperplasia and hypertrophy, as seen in obese with pre-diabetes. Indeed, here we provide for metformin therapy an important regulative function on the control of these pathogenic mechanisms, by significant reduction of inflammatory/oxidative stress markers, as CRP, IL6, TNFα, and nitrotyrosine(1,16), and by down regulation of circulating miR-195 and miR-27,(21,25). Finally, an inverse correlation exists between miR-195, miR-27 and cardiovascular parameters as IMT, LVEF, LVM and MPI.…”

Metformin protects against sevoflurane‑induced neuronal apoptosis through the S1P1 and ERK signaling pathways

“…Metformin was first clinically used as a hypoglycemic agent (18,19). Subsequent studies demonstrated that metformin had different effects on various tissues and systems (29,30). Metformin was revealed to prevent the sevoflurane-induced apoptosis of neurons, which was reversed by a specific S1P1 antagonist (31).…”

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

“…Consequently, measure of quantity and detection of functionality of EPCs could a powerful diagnostic tool for CV risk stratification and prediction of CV events. On the other hand, there are serious expectations regarding that the clinical outcomes in diabetics could be improved through modification of endothelial function and inducing cardioprotection via restoring number and function of EPCs with metformin therapy, glucagon-like peptide 1-receptor agonists (liraglutide, exenatide), dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin) and sodium glucose cotransporter-2 (SGLT2) inhibitors, which appeared to be effective in suppression of anti-angiogenic miRNAs [26][27][28]. Although exact protective mechanisms for the EPCs in pre-diabetes and diabetes remains elusive, EPCs dysfunction is promising target for improving clinical outcomes in diabetics.…”