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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:104.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Oral Insulin Supplementation Attenuates Atherosclerosis Progression in Apolipoprotein E-Deficient Mice

Raanan Shamir; Naim Shehadeh; Mira Rosenblat; Orly Eshach-Adiv; Raymond Coleman; Marielle Kaplan; Shadi Hamoud; Sophie Lischinsky; Tony Hayek

From the Pediatric Gastroenterology and Nutrition Unit (R.S., O.E.A.) and Juvenile Diabetes Unit (N.S.), Meyer Children’s Hospital of Haifa; Department of Medicine E (S.H., T.H.) and Department of Biochemistry (S.L.), Rambam Medical Center; and Lipid Research Laboratory (M.R., M.K., T.H.) and Department of Anatomy and Cell Biology (R.C.), Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Correspondence to Raanan Shamir, MD, Division of Pediatric Gastroenterology and Nutrition, Meyer Children’s Hospital of Haifa, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E-mail shamirr{at}netvision.net.il

Objective— The role of insulin in atherosclerosis progression in diabetes is uncertain. We examined the effects of oral insulin supplementation on atherogenesis in apolipoprotein E-deficient (E⁰) mice.

Methods and Results— One-month-old male E⁰ mice were orally supplemented with human insulin (0.1, 0.5, and 1 U/mL) or placebo for 3 months. At the end of the study, serum and macrophage oxidative stress and atherosclerosis progression were studied. Insulin reduced lesion size by 22% to 37% (P<0.05) in all study groups. Lipid peroxides serum levels were 18% lower (P<0.01), and serum paraoxonase activity was 30% higher (P<0.01) in mice supplemented with 1.0 U/mL insulin compared with controls. Insulin reduced mouse peritoneal macrophage (MPM) lipid peroxides content and superoxide anion release by up to 44% and 62%, respectively (P<0.01). In addition, oral insulin reduced MPM cholesterol content and cholesterol biosynthesis by up to 36% and 53%, respectively (P<0.01). In vitro incubation of E⁰ mice MPM with increasing insulin concentrations (0 to 100 µU/mL) resulted in a dose-dependent reduction of cholesterol synthesis by up to 66% (P<0.05).

Conclusions— In E⁰ mice, oral insulin supplementation attenuates the atherosclerotic process. This may be attributable to insulin-mediated reduction of oxidative stress in serum and macrophages as well as reduction in macrophage cholesterol content.

Key Words: oral insulin • atherosclerosis • oxidative stress • paraoxonase • macrophages

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