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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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

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Protein Tyrosine Phosphatases
Antisense Oligonucleotides
Adiponectin
Haplorhini
Insulin Resistance
Insulin
Glucose Tolerance Test
Type 2 Diabetes Mellitus
Adipose Tissue
Obesity
Messenger RNA
Liver
Inhibition (Psychology)
Macaca mulatta
Primates
Hepatocytes
Rodentia
Fasting
Triglycerides

ASJC Scopus subject areas

  • Endocrinology

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Inhibition of protein tyrosine phosphatase-IB with antisense oligonucleotides iMproves insulin sensitivity and increases adiponectin concentrations in monkeys. / Swarbrick, Michael M.; Havel, Peter J; Levin, Arthur A.; Bremer, Andrew A.; Stanhope, Kimber; Butler, Madeline; Booten, Sheri L.; Graham, James L.; McKay, Robert A.; Murray, Susan F.; Watts, Lynnetta M.; Monia, Brett P.; Bhanot, Sanjay.

In: Endocrinology, Vol. 150, No. 4, 04.2009, p. 1670-1679.

Research output: Contribution to journalArticle

Swarbrick, MM, Havel, PJ, Levin, AA, Bremer, AA, Stanhope, K, Butler, M, Booten, SL, Graham, JL, McKay, RA, Murray, SF, Watts, LM, Monia, BP & Bhanot, S 2009, 'Inhibition of protein tyrosine phosphatase-IB with antisense oligonucleotides iMproves insulin sensitivity and increases adiponectin concentrations in monkeys', Endocrinology, vol. 150, no. 4, pp. 1670-1679. https://doi.org/10.1210/en.2008-0885
Swarbrick, Michael M. ; Havel, Peter J ; Levin, Arthur A. ; Bremer, Andrew A. ; Stanhope, Kimber ; Butler, Madeline ; Booten, Sheri L. ; Graham, James L. ; McKay, Robert A. ; Murray, Susan F. ; Watts, Lynnetta M. ; Monia, Brett P. ; Bhanot, Sanjay. / Inhibition of protein tyrosine phosphatase-IB with antisense oligonucleotides iMproves insulin sensitivity and increases adiponectin concentrations in monkeys. In: Endocrinology. 2009 ; Vol. 150, No. 4. pp. 1670-1679.
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AU - Stanhope, Kimber

AU - Butler, Madeline

AU - Booten, Sheri L.

AU - Graham, James L.

AU - McKay, Robert A.

AU - Murray, Susan F.

AU - Watts, Lynnetta M.

AU - Monia, Brett P.

AU - Bhanot, Sanjay

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