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Insulin Sensitivity is Enhanced by CGMP-mediated MAPK Inhibition in Rat Adipocytes

Bradykinin (BK) acts through eNOS to reduce MAPK-mediated feedback inhibition of
insulin signalling. Preliminary data suggest that the sGC-cGMP-PKG pathway, a prominent NO target, is involved. Our present study aimed to support the role of this pathway with atrial natriuretic
peptide (ANP), which uses a receptor associated GC (NPR-A) to generate cGMP.
We found that treating adipocytes with ANP mimicked BK effects on insulin-stimulated
glucose uptake, Tyr-IRS-1 and Akt/PKB phosphorylation, as well as JNK and ERK1/2 inhibition.
These outcomes depended on GC-cGMP-PKG signalling since A71915 (NPR-A antagonist), and KT-5823 (PKG inhibitor), completely abrogated them, while zaprinast (phosphodiesterase inhibitor), prolonged ANP actions. Furthermore, decreased MAPK phosphorylation was independent of
upstream kinase activity, suggesting that MAPK phosphatases may be involved.
These data indicate that BK and ANP act through the GC-cGMP-PKG pathway to potentiate insulin signalling via attenuated feedback inhibition. Stimulating the GC-cGMP-PKG pathway may, therefore, be a promising therapy for T2DM.

Identiferoai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/18962
Date16 February 2010
CreatorsThomas, Garry
ContributorsFantus, I. George
Source SetsLibrary and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada
Languageen_ca
Detected LanguageEnglish
TypeThesis

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