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Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys

Department of Molecular Biosciences (M.M.S., P.J.H., K.L.S., J.L.G.), School of Veterinary Medicine, Department of Nutrition (M.M.S., P.J.H., K.L.S., J.L.G.), and Department of Pediatrics (A.A.B.), School of Medicine, University of California, Davis, Davis, California 95616; and Isis Pharmaceuticals Inc. (A.A.L., M.B., S.L.B., R.A.M., S.F.M., L.M.W., B.P.M., S.B.), Carlsbad, California 92008

Address all correspondence and requests for reprints to: Sanjay Bhanot, M.D., Ph.D., Vice President Metabolic Diseases R&D, Isis Pharmaceuticals, Inc., 1896 Rutherford Road, Carlsbad, California 92008. E-mail: sbhanot{at}isisph.com.

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = –0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.