Hyperinsulinemia does not change atherosclerosis development in apolipoprotein E null mice

Area of Science:

• Cardiovascular Research
• Metabolic Syndrome
• Atherosclerosis Pathogenesis

Background:

• Hyperinsulinemia is linked to metabolic syndrome and cardiovascular disease.
• The direct role of hyperinsulinemia in atherosclerosis development remains unclear.
• Insulin resistance is a known contributor to atherosclerosis.

Purpose of the Study:

• To investigate the causal role of hyperinsulinemia in atherosclerosis development.
• To determine if elevated insulin levels accelerate atherosclerosis in the absence of significant insulin resistance.
• To elucidate the contribution of impaired insulin clearance to hyperinsulinemia and atherosclerosis.

Main Methods:

• Utilized apolipoprotein E (Apoe) null mice with targeted insulin receptor (Insr) gene knockout.
• Compared Insr haploinsufficient/Apoe null mice with Apoe null littermates.
• Assessed plasma insulin, glucose tolerance, insulin sensitivity, insulin signaling, and atherosclerotic lesion development.

Main Results:

• Insr haploinsufficient/Apoe null mice exhibited significant hyperinsulinemia due to impaired insulin clearance.
• No differences were observed in glucose tolerance, insulin sensitivity, plasma lipids, or blood pressure between groups.
• Atherosclerotic lesion size and cholesterol abundance were similar in both groups up to 52 weeks.

Conclusions:

• Hyperinsulinemia alone, without significant insulin resistance or altered lipids/blood pressure, does not promote atherosclerosis.
• Impaired insulin clearance is a primary driver of hyperinsulinemia in this model.
• These findings highlight the importance of insulin resistance in the link between metabolic dysfunction and cardiovascular disease.