PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.
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.
Zinker
Bradley A
BA
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. bradley.zinker@abbott.com
Rondinone
Cristina M
CM
Trevillyan
James M
JM
Gum
Rebecca J
RJ
Clampit
Jill E
JE
Waring
Jeffrey F
JF
Xie
Nancy
N
Wilcox
Denise
D
Jacobson
Peer
P
Frost
Leigh
L
Kroeger
Paul E
PE
Reilly
Regina M
RM
Koterski
Sandra
S
Opgenorth
Terry J
TJ
Ulrich
Roger G
RG
Crosby
Seth
S
Butler
Madeline
M
Murray
Susan F
SF
McKay
Robert A
RA
Bhanot
Sanjay
S
Monia
Brett P
BP
Jirousek
Michael R
MR
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
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