Oral insulin supplementation attenuates atherosclerosis progression in apolipoprotein E-deficient mice.
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 (E(0)) mice.


RESULTS
One-month-old male E(0) 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 E(0) mice MPM with increasing insulin concentrations (0 to 100 micro U/mL) resulted in a dose-dependent reduction of cholesterol synthesis by up to 66% (P<0.05).


CONCLUSIONS
In E(0) 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.
Shamir
Raanan
R
Division of Pediatric Gastroenterology and Nutrition, Meyer Children's Hospital of Haifa, Rambam Medical Center, Israel. shamirr@netvision.net.il
Shehadeh
Naim
N
Rosenblat
Mira
M
Eshach-Adiv
Orly
O
Coleman
Raymond
R
Kaplan
Marielle
M
Hamoud
Shadi
S
Lischinsky
Sophie
S
Hayek
Tony
T
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000188:drug therapy; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D043303:Aryldialkylphosphatase; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000097:blood; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000097:blood; D017737:Macrophages, Peritoneal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects
D001057:Apolipoproteins E; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D002784:Cholesterol; D004950:Esterases; D043303:Aryldialkylphosphatase