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cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle
Citation
Genders, AJ and Bradley, EA and Rattigan, S and Richards, SM, cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle, American Journal of Physiology: Endocrinology and Metabolism, 301, (2) pp. E342-E350. ISSN 0193-1849 (2011) [Refereed Article]
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Copyright Statement
Copyright © 2011 The American Physiological Society
DOI: doi:10.1152/ajpendo.00691.2010
Abstract
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.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | cyclic guanosine monophosphate; blood flow; insulin and glucose delivery to muscle; microvascular blood flow |
| Research Division: | Medical and Health Sciences |
| Research Group: | Clinical Sciences |
| Research Field: | Endocrinology |
| Objective Division: | Health |
| Objective Group: | Clinical Health (Organs, Diseases and Abnormal Conditions) |
| Objective Field: | Diabetes |
| UTAS Author: | Genders, AJ (Ms Amanda Genders) |
| UTAS Author: | Bradley, EA (Miss Eloise Bradley) |
| UTAS Author: | Rattigan, S (Professor Stephen Rattigan) |
| UTAS Author: | Richards, SM (Dr Stephen Richards) |
| ID Code: | 71815 |
| Year Published: | 2011 |
| Web of Science® Times Cited: | 9 |
| Deposited By: | Menzies Institute for Medical Research |
| Deposited On: | 2011-08-09 |
| Last Modified: | 2017-11-06 |
| Downloads: | 0 |
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