Metformin Delays the Development of Atherosclerosis in Type 1 Diabetes Mellitus via the Methylglyoxal Pathway.

Abstract

IntroductionThe aim of our study was to determine the effect of metformin administration on juvenile type 1 diabetes mellitus and atherosclerosis in apolipoprotein E null (ApoE−/−) mice and to explore the mechanism involved.MethodsEighteen male ApoE−/− mice were injected with streptozotocin to induce diabetes (diabetic group) and 18 mice who received no streptozotocin injection were assigned to the control (non-diabetic) group. Six mice in each group were then orally administered metformin, simvastatin, or vehicle, respectively, following which the mice were euthanized and tissue samples collected.ResultsFasting plasma glucose, low-density lipoprotein-cholesterol, and triglyceride concentrations were significantly higher in the three diabetic groups than in the three non-diabetic groups. Plasma N∈-(carboxymethyl)lysine and N∈-(carboxyethyl)lysine concentrations were higher in the diabetic mice than in the non-diabetic mice, but metformin treatment reduced these concentrations more effectively than simvastatin. All three diabetic groups demonstrated obvious arterial plaques, but these were largest in the vehicle-treated diabetic group. The expression of extracellular nitric oxide synthase was highest in the simvastatin-treated non-diabetic group, and in diabetic mice it was higher in the simvastatin-treated group than in the other two groups. No significant expression of AMP-activated protein kinase (AMPK) was measured in the three diabetic groups, but a low level of AMPK expression was detected in the non-diabetic groups.ConclusionsMetformin can limit the development of atherosclerosis secondary to diabetes in young diabetic mice. A possible mechanism is the removal of methylglyoxal, thereby reducing the formation of advanced glycation endproducts, rather than by lowering the blood glucose level.FundingThis work was supported by the National Natural Science Foundation of China (81901106) and Jinan clinical medical science and technology innovation plan (201907002).