title: PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.
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 HbA(1C). 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 p50alpha, were increased and PI3-kinase p85alpha 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.
authors.affiliation: Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. bradley.zinker@abbott.com
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Rondinone
authors.forename: James M
authors.initials: JM
authors.lastname: Trevillyan
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Gum
authors.forename: Jill E
authors.initials: JE
authors.lastname: Clampit
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.forename: Nancy
authors.initials: N
authors.lastname: Xie
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.forename: Peer
authors.initials: P
authors.lastname: Jacobson
authors.forename: Leigh
authors.initials: L
authors.lastname: Frost
authors.forename: Paul E
authors.initials: PE
authors.lastname: Kroeger
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Sandra
authors.initials: S
authors.lastname: Koterski
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Opgenorth
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: Seth
authors.initials: S
authors.lastname: Crosby
authors.forename: Madeline
authors.initials: M
authors.lastname: Butler
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murray
authors.forename: Robert A
authors.initials: RA
authors.lastname: McKay
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003433:Crosses, Genetic; D003920:Diabetes Mellitus / Q000097:blood* / Q000188:drug therapy; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008099:Liver / Q000033:anatomy & histology; D051379:Mice; D008820:Mice, Obese; D009765:Obesity; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D018075:RNA, Complementary / Q000235:genetics; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020319:Oligodeoxyribonucleotides, Antisense; D018075:RNA, Complementary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse