Propranolol and low-dose isoproterenol ameliorate insulin resistance, enhance β-arrestin2 signaling, and reduce cardiac remodeling in high-fructose, high-fat diet-fed mice: Comparative study with metformin

Aims: beta-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate beta-arrestin2 signaling. The current study examined the effects of the beta-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on beta-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. Materials and methods: Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic beta-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac beta-arrestin2 signaling were then compared among groups. Key findings: HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic beta-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac beta-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced beta-arrestin2 signaling with variable efficacies. Significance: Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating beta-arrestin2 signaling activity. Therefore, beta-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.

Automated summary

This study examined the effects of propranolol and L-D-ISOPROT on β-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet-fed mice. The results showed that these two drugs, like metformin, can reduce insulin resistance and cardiac remodeling. Modulation of β-arrestin2 signaling may be a promising strategy for the treatment of insulin resistance.