Hyperinsulinemia Does Not Change Atherosclerosis Development in Apolipoprotein E Null Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 5; pp. 1124 - 1131
• Main Authors: Rask-Madsen, Christian, Buonomo, Erica, Li, Qian, Park, Kyoungmin, Clermont, Allen C, Yerokun, Oluwatobi, Rekhter, Mark, King, George L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-05-2012; Lippincott Williams & Wilkins
• Subjects: Alcoholism and acute alcohol poisoning; Animals; Apolipoproteins E - blood; Apolipoproteins E - genetics; Atherosclerosis (general aspects, experimental research); Atherosclerosis - blood; Atherosclerosis - etiology; Atherosclerosis - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Gene Expression Regulation; Hyperinsulinism - blood; Hyperinsulinism - complications; Hyperinsulinism - genetics; Insulin Receptor Substrate Proteins - biosynthesis; Insulin Receptor Substrate Proteins - genetics; Insulin Resistance; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Toxicology; Endocrinopathy; Hyperinsulinemia; Diabetes mellitus; Rodentia; Metabolic diseases; Cardiovascular disease; genetically altered mice; Vascular disease; Target tissue resistance; Signal transduction; Vertebrata; Mammalia; Mouse; Apolipoprotein E; Animal; Atherosclerosis; Insulin resistance
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.111.239558

OBJECTIVE—To determine the contribution of hyperinsulinemia to atherosclerosis development.
METHODS AND RESULTS—Apolipoprotein E (Apoe) null mice that had knockout of a single allele of the insulin receptor (Insr) gene were compared with littermate Apoe null mice with intact insulin receptors. Plasma insulin levels in Insr haploinsufficient/Apoe null mice were 50% higher in the fasting state and up to 69% higher during a glucose tolerance test, but glucose tolerance was not different in the 2 groups. C-peptide levels, insulin sensitivity, and postreceptor insulin signaling in muscle, liver, fat, and aorta were not different between groups, whereas disappearance in plasma of an injected insulin analog was delayed in Insr haploinsufficient/Apoe null mice, indicating that impaired insulin clearance was the primary cause of hyperinsulinemia. No differences were observed in plasma lipids or blood pressure. Despite the hyperinsulinemia, atherosclerotic lesion size was not different between the 2 groups at time points up to 52 weeks of age when measured as en face lesion area in the aorta, cross-sectional plaque area in the aortic sinus, and cholesterol abundance in the brachiocephalic artery.
CONCLUSION—Hyperinsulinemia, without substantial vascular or whole-body insulin resistance and without changes in plasma lipids or blood pressure, does not change susceptibility to atherosclerosis.