PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice

Bradley A. Zinker, Cristina M. Rondinone, James M. Trevillyan, Rebecca J. Gum, Jill E. Clampit, Jeffrey F. Waring, Nancy Xie, Denise Wilcox, Peer Jacobson, Leigh Frost, Paul E. Kroeger, Regina M. Reilly, Sandra Koterski, Terry J. Opgenorth, Roger G. Ulrich, Seth Crosby, Madeline Butler, Susan F. Murray, Robert A. McKay, Sanjay BhanotBrett P. Monia, Michael R. Jirousek

Research output: Contribution to journalArticle

373 Scopus citations

Abstract

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA1C. Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50α, were increased and PI3-kinase p85α expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes.

Original languageEnglish
Pages (from-to)11357-11362
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number17
DOIs
StatePublished - Aug 20 2002
Externally publishedYes

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    Zinker, B. A., Rondinone, C. M., Trevillyan, J. M., Gum, R. J., Clampit, J. E., Waring, J. F., Xie, N., Wilcox, D., Jacobson, P., Frost, L., Kroeger, P. E., Reilly, R. M., Koterski, S., Opgenorth, T. J., Ulrich, R. G., Crosby, S., Butler, M., Murray, S. F., McKay, R. A., ... Jirousek, M. R. (2002). PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America, 99(17), 11357-11362. https://doi.org/10.1073/pnas.142298199