Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways

• To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110 alpha catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110 alpha but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.

Nyckelord

1-Phosphatidylinositol 3-Kinase/biosynthesis

Animals

Blood Glucose/metabolism

Blotting

Western

Body Weight/physiology

Electrocardiography

Female

Fibrosis

Gene Expression Regulation

Enzymologic/physiology

Heart/anatomy & histology/*physiology

Hemodynamic Processes/physiology

Hyperinsulinism/*physiopathology

Immunohistochemistry

Insulin/blood/*physiology

Mitogen-Activated Protein Kinases/metabolism

Organ Size/physiology

Proto-Oncogene Proteins c-akt/biosynthesis

Rats

Rats

Sprague-Dawley

Receptors

Angiotensin/*biosynthesis

Receptors

G-Protein-Coupled/metabolism

Reverse Transcriptase Polymerase Chain Reaction

Signal Transduction/*physiology

Ventricular Function

Left/physiology

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