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cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle

journal contribution
posted on 2023-05-17, 07:03 authored by Genders, AJ, Bradley, EA, Stephen RattiganStephen Rattigan, Stephen RichardsStephen Richards
There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU·min(-1)·kg(-1)) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity.

History

Publication title

American Journal of Physiology: Endocrinology and Metabolism

Volume

301

Pagination

E342-E350

ISSN

0193-1849

Department/School

Menzies Institute for Medical Research

Publisher

Amer Physiological Soc

Place of publication

9650 Rockville Pike, Bethesda, USA, Md, 20814

Rights statement

Copyright © 2011 The American Physiological Society

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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