Abstract
Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.
Highlights
Insulin binds to the alpha (α) subunit of insulin receptor (IR) in the cell membrane, and triggers the tyrosine kinase activity in the β subunit of IR by phosphorylation of the substrates (IRS1 and IRS2) [1, 2]
Glucose excursion was determined by GTT in nine-week old mice on a 60% fat diet inoculated with early gene 4 open reading frame 1 (E4orf1) expressing retrovirus or control group of mice
Despite better glucose clearance in these HF fed mice, E4orf1 expression had impaired proximal insulin signaling in epidydimal fat depot as observed by the reduced phospho-tyrosine expression of IR (Fig 2A)
Summary
Insulin binds to the alpha (α) subunit of IR in the cell membrane, and triggers the tyrosine kinase activity in the β subunit of IR by phosphorylation of the substrates (IRS1 and IRS2) [1, 2]. This constitutes the ‘proximal’ insulin signaling, which is followed by ‘distal’ insulin signaling that involves activation of the Ras-MAPK pathway and the activation of phosphatidylinositol-3-kinase (PI3K). The activation of PI3K pathway leads to Akt activation and glucose transporter (GLUT)-4 mediated glucose uptake [3, 4]. ENPP1 interacts with the α subunit of IR [5], leading to PLOS ONE | DOI:10.1371/journal.pone.0161275 August 18, 2016
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