Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model.

Almudena Gómez-Hernández,Vicente Lahera,Tamara González-Illanes,Óscar Escribano,Paula González-López,Manuel Benito,Gema García-Gómez,Natalia De Las Heras,Jorge Infante-Menéndez,Andrea R López-Pastor

doi:10.3390/cells10082035

Abstract

Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.

Highlights

IntroductionObesity is a chronic and multifactorial disease characterized by an increased body weight with excessive fat accumulation, as well as low grade inflammation [2,3]
As occurs with antidiabetic drugs, in the current paper, we demonstrate that a liver-specific gene therapy approach with IRA ameliorates the diabetic phenotype and improves vascular damage observed in insulin receptor knockout (iLIRKO) mice
Our results suggest that severe hepatic insulin resistance expanded to cardiovascular tissues, such as the heart and artery aorta

Summary

Introduction

Obesity is a chronic and multifactorial disease characterized by an increased body weight with excessive fat accumulation, as well as low grade inflammation [2,3]. This condition is associated with insulin resistance, type 2 diabetes mellitus (T2DM). Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice

Methods

Results

Discussion

Conclusion