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

The lipid phosphatase SH2 domaincontaining 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 feasability of such a strategy should be examined further.