Table 1.

Various effects of metformin on endothelial dysfunction.

Subject	Beneficial Effect	Adverse Effect	Mechanism	Reference
Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model)	Normalized endothelial function	--	Suppression of vasoconstrictor prostanoids in mesenteric arteries	[80,81,82]
Spontaneously-hypertensive-rats (SHR)	Blood pressure reduction and endothelial-dependent relaxation improvement		Upregulation of NO and, in particular, EDHF	[83]
In vito; streptozotocin diabetes model in vivo	Tissue-intact and cultured vascular endothelial cells protection from hyperglycemia/ROS-induced dysfunction	--	Attenuation of hyperglycemia-induced ROS production in aorta-derived endothelial cell cultures; hyperglycemia-induced endothelial mitochondrial dysfunction prevention (oxygen consumption rate reduction)	[84]
HUVECs; C57/BL6 male mice	Prevention of methylglyoxal-induced apoptosis	--	MGO-induced HUVEC apoptosis prevention; apoptosis-associated biochemical changes inhibition (loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3); attenuation of MGO-induced mitochondrial morphological alterations in a dose-dependent manner	[85]
Cultured smooth muscle cells of the human aorta	Delay of cell aging	--	Metformin-activated AMP upregulates p53, and IF116 suppresses cell proliferation and migration. In cultured (early passage) human aortic endothelial cells, metformin activates AMPKa and induces telomere expansion of hTERT, delaying cell aging	[61]
T2D patients with stable coronary heart disease	Lowering of plasma sVCAM-1 (553 ± 148 vs. 668 ± 170 µg/L, p = 0.004) and elevation of ADMA (0.53 ± 0.09 vs. 0.48 ± 0.08 µM, p = 0.01)	--	Change of VCAM1 and asymmetric dimethylarginine (ADMA) level	[86]
T2D patients treated with insulin	About 34% reduction in the risk of CV morbidity and mortality	--	There was a reduction in the levels of vWF, sVCAM-1, t-PA, PAI-1, CRP, and sICAM-1. No effects on urinary albumin excretion or sE-selectin were observed.	[87,88]
Women with obesity and type 2 diabetes, drug-naïve	Nutritive microvascular reactivity improvement at the capillary level	Unexpected increase in tumor necrosis factor-α	Reduction of weight, plasma glucose, total cholesterol, HDL-c, LDL-c, and dipeptidyl peptidase-4 activity	[89,90,91]
Patients with ST-segment elevation MI	Alanine level elevation and lowering of the phospholipid content in very large HDL particles	--	Triglyceride levels in HDL and several HDL subfractions were measured 24 h post-MI; the composition of XS-VLDL (24 h post-MI) and L-LDL (baseline) was associated with abnormal LV function 4 months post-MI.	[92]