TY - JOUR
T1 - PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice
AU - Zinker, Bradley A.
AU - Rondinone, Cristina M.
AU - Trevillyan, James M.
AU - Gum, Rebecca J.
AU - Clampit, Jill E.
AU - Waring, Jeffrey F.
AU - Xie, Nancy
AU - Wilcox, Denise
AU - Jacobson, Peer
AU - Frost, Leigh
AU - Kroeger, Paul E.
AU - Reilly, Regina M.
AU - Koterski, Sandra
AU - Opgenorth, Terry J.
AU - Ulrich, Roger G.
AU - Crosby, Seth
AU - Butler, Madeline
AU - Murray, Susan F.
AU - McKay, Robert A.
AU - Bhanot, Sanjay
AU - Monia, Brett P.
AU - Jirousek, Michael R.
PY - 2002/8/20
Y1 - 2002/8/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037143754&partnerID=8YFLogxK
U2 - 10.1073/pnas.142298199
DO - 10.1073/pnas.142298199
M3 - Article
C2 - 12169659
AN - SCOPUS:0037143754
SN - 0027-8424
VL - 99
SP - 11357
EP - 11362
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -