Inhibition of protein tyrosine phosphatase-IB with antisense oligonucleotides iMproves insulin sensitivity and increases adiponectin concentrations in monkeys

Michael M. Swarbrick, Peter J Havel, Arthur A. Levin, Andrew A. Bremer, Kimber Stanhope, Madeline Butler, Sheri L. Booten, James L. Graham, Robert A. McKay, Susan F. Murray, Lynnetta M. Watts, Brett P. Monia, Sanjay Bhanot

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48 Scopus citations

Abstract

Protein tyrosine phosphatase (PTP)-IB 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.

Original languageEnglish (US)
Pages (from-to)1670-1679
Number of pages10
JournalEndocrinology
Volume150
Issue number4
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Endocrinology

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    Swarbrick, M. M., Havel, P. J., Levin, A. A., Bremer, A. A., Stanhope, K., Butler, M., Booten, S. L., Graham, J. L., McKay, R. A., Murray, S. F., Watts, L. M., Monia, B. P., & Bhanot, S. (2009). Inhibition of protein tyrosine phosphatase-IB with antisense oligonucleotides iMproves insulin sensitivity and increases adiponectin concentrations in monkeys. Endocrinology, 150(4), 1670-1679. https://doi.org/10.1210/en.2008-0885