The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance.

Authors:
Ersilia Cipolletta
Ersilia Cipolletta
Department of Clinical Medicine
Italy
Alfonso Campanile
Alfonso Campanile
Ospedale Maggiore Policlinico
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
Dario Leosco
Dario Leosco
University of Naples Federico II
Napoli | Italy
Pietro Campiglia
Pietro Campiglia
University of Salerno
Bruno Trimarco
Bruno Trimarco
Federico II University
Napoli | Italy
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy

Cardiovasc Res 2009 Dec 20;84(3):407-15. Epub 2009 Jul 20.

Dipartimento di Medicina Clinica, Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Università Federico II, Via Pansini 5, 80131 Naples, Italy.

Aims: Insulin (Ins) resistance (IRES) associates to increased cardiovascular risk as observed in metabolic syndrome. Chronic stimulation of beta-adrenergic receptors (betaAR) due to exaggerated sympathetic nervous system activity is involved in the pathogenesis of IRES. The cellular levels of G protein coupled receptor kinase 2 (GRK2) increase during chronic betaAR stimulation, leading to betaAR desensitization. We tested the hypothesis that GRK2 plays a role in betaAR-induced IRES.

Methods And Results: We evaluated Ins-induced glucose uptake and signalling responses in vitro in cell overexpressing the beta(2)AR, the GRK2, or the catalytically dead mutant GRK2-DN. In a model of increased adrenergic activity, IRES and elevated cellular GRK2 levels, the spontaneously hypertensive rats (SHR) we performed the intravenous glucose tolerance test load. To inhibit GRK2, we synthesized a peptide based on the catalytical sequence of GRK2 conjugated with the antennapedia internalization sequence (Ant-124). Ins in human kidney embryonic (HEK-293) cells causes rapid accumulation of GRK2, tyrosine phosphorylation of Ins receptor substrate 1 (IRS1) and induces glucose uptake. In the same cell type, transgenic beta(2)AR overexpression causes GRK2 accumulation associated with significant deficit of IRS1 activation and glucose uptake by Ins. Similarly, transgenic GRK2 overexpression prevents Ins-induced tyrosine phosphorylation of IRS1 and glucose uptake, whereas GRK2-DN ameliorates glucose extraction. By immunoprecipitation, GRK2 binds IRS1 but not the Ins receptor in an Ins-dependent fashion, which is lost in HEK-GRK2 cells. Ant-124 improves Ins-induced glucose uptake in HEK-293 and HEK-GRK2 cells, but does not prevent GRK2/IRS1 interaction. In SHR, Ant-124 infusion for 30 days ameliorates IRES and IRS1 tyrosine phosphorylation.

Conclusion: Our results suggest that GRK2 mediates adrenergic IRES and that inhibition of GRK2 activity leads to increased Ins sensitivity both in cells and in animal model of IRES.

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http://dx.doi.org/10.1093/cvr/cvp252DOI Listing
December 2009
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32 Citations
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References

(Supplied by CrossRef)
Acute noradrenergic activation induces insulin resistance in human skeletal muscle
Lembo et al.
Am J Physiol 1994
Polymorphism in the 5’-leader cistron of the beta2-adrenergic receptor gene associated with obesity and type 2 diabetes
Yamada et al.
J Clin Endocrinol Metab 1999

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