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

Abstract

Introduction: The 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. Methods: Eighteen 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. Results: Fasting 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. Conclusions: Metformin 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. Funding: This work was supported by the National Natural Science Foundation of China (81901106) and Jinan clinical medical science and technology innovation plan (201907002).