Effects of Metformin on Skin Microcirculation and Inflammatory Markers in a Rat Model of Metabolic Syndrome

Current evidence supports the existence of a clear, at least bidirectional, relationship between endothelial dysfunction and insulin resistance that may link cardiovascular and metabolic diseases suggest using therapies proven to reduce atherosclerotic events and microvascular disease in parallel wherever feasible. The aim of this study was to assess the effects of the insulin sensitizer, metformin, on skin microcirculation in an experimental model of metabolic syndrome. 36 Young female rats were randomly assigned into control group (CG) fed on standard rat show, fructose induced insulin resistance group (FG) fed on fructose enriched show ( 60 % of caloric intake) for 2 months fructose induced insulin resistance + metformin group ( FMG) fed fructose enriched chow for the whole 2 month given metformin 300mg/kg daily for 2 weeks in drinking water after 6 weeks of taking the high fructose diet. After 2 months, some metabolic parameters, inflammatory markers systolic blood pressure SBP were measured and skin microcirculation was assessed in hairless ear skin of the rat by Laser Doppler Flowmeter (LDF). Parameters of microcirculation included skin blood flow in perfusion units (PU), frequency of vasomotion waves, (frequency 1: 1-3 cycles/min (endothelial activity), frequency 2: 3-5 cycles/min (sympathetic activity), frequency 3: 5-20 cycles/min (vascular myogenic Activity)) the Power of vasomotion (PU) in relation to the recorded frequencies . Parameters of microcirculation were measured at 30°C and after local heating of the skin to 44°C. We found that treatment with metformin significantly decreased serum glucose, serum insulin, homeostasis model of insulin resistance HOMAIR, serum triglycerides TGs, levels of nitric oxide NO, high-sensitivity C reactive protein hsCRP and tumor necrosis factor-alpha TNF- α (P 0.05) and significantly increased high density lipoprotein cholesterol HDL-C (P 0.05)compared to FG. No significant improvement was found in the levels of serum total cholesterol TC, low density lipoprotein – cholesterol LDL-C, body mass index BMI and SBP. Regarding parameters of microcirculation, metformin treatment for 2 weeks increased significantly the levels of percent change between blood flow at 30°C and after local heating of the skin to 44°C, levels of vasomotion frequency 3 at 30°C and levels of frequency1 and 2 at 44°C as compared to FG ( P 0.05). Regarding the power of vasomotion, the levels of power 1 at 30°C and that of power 3 at 44°C showed significant improvement with metformin treatment ( P 0.05). Metformin improves insulin sensitivity, decreases insulin levels, controls hyperglycemia, improves lipid profiles, restores the inflammatory markers has beneficial vascular effects through improvement in microvascular reactivity to heat and partial improvement of vasomotion frequency and power. This supports the concept of the central role of metformin as a first-line therapeutic to treat patients with metabolic syndrome in order to protect against endothelial dysfunction associated with insulin resistance.