Antisense oligonucleotides against the lipid phosphatase SHIP2 improve muscle insulin sensitivity in a dietary rat model of the metabolic syndrome

Abstract

The lipid phosphatase SH2 domain-containing lipid phosphatase (SHIP2) has been implicated in the regulation of insulin sensitivity, but its role in the therapy of insulin-resistant states remains to be defined. Here, we examined the effects of an antisense oligonucleotide (AS) therapy directed against SHIP2 on whole body insulin sensitivity and insulin action in liver and muscle tissue in a dietary rodent model of the metabolic syndrome, the high-fat-fed (HF) rat. Whole body insulin sensitivity was examined in vivo by insulin tolerance tests before and after the intraperitoneal application of an AS directed against SHIP2 (HF-SHIP2-AS) or a control AS (HF-Con-AS) in HF rats. Insulin action in liver and muscle was assayed by measuring the activation of protein kinase B (Akt) and insulin receptor substrate (IRS)-1/2 after a portal venous insulin bolus. SHIP2 mRNA and protein content were quantified in these tissues by real-time PCR and immunoblotting, respectively. In HF-SHIP2-AS, whole body glucose disposal after an insulin bolus was markedly elevated compared with HF-Con-AS. In liver, insulin activated Akt similarly in both groups. In muscle, insulin did not clearly activate Akt in HF-Con-AS animals, whereas insulin-induced Akt phosphorylation was sustained in SHIP2-AS-treated rats. IRS-1/2 activation did not differ between the experimental groups. SHIP2 mRNA and protein content were markedly reduced only in muscle. In standard diet-fed controls, SHIP2-AS reduced SHIP2 protein levels in liver and muscle, but it had no significant effect on insulin sensitivity. We conclude that treatment with SHIP2-AS can rapidly improve muscle insulin sensitivity in dietary insulin resistance. The long-term feasibility of such a strategy should be examined further.

Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2

“…These in vitro studies agree well with previous reports using siRNA and the dominant negative inhibition of SHIP2 (Fukui et al. , 2005; Buettner et al. , 2007; Grempler et al.…”

Regulation of MAP Kinase–Directed Mitogenic and Protein Kinase B–Mediated Signaling by Cannabinoid Receptor Type 1 in Skeletal Muscle Cells

“…Another possible explanation may involve SR141716 “priming” the cell for stimulation by insulin by disrupting the inhibitory environment acting on PKB and ERK1/2 under basal conditions. For instance, this may involve relieving the inhibitory action of various phosphatases that can negatively regulate insulin responses (38–43). We have observed that SR141716 does not alter expression of phosphatase and tensin homolog (PTEN) in L6 myotubes (data not shown), although the possibility that it may change the expression and/or activity of other important protein phosphatase(s) such as protein tyrosine phosphatase 1B (PTP-1B) or Src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1) cannot be excluded.…”

Skeletal Muscle–Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues

“…5E). The levels of two lipid phosphatases known to modify Akt phosphorylation (PTEN and SHIP2) (21,22) were unchanged in SMLPL Ϫ/Ϫ mice (Fig. 5F).…”