Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys.
Protein tyrosine phosphatase (PTP)-1B 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.
Swarbrick
Michael M
MM
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA.
Havel
Peter J
PJ
Levin
Arthur A
AA
Bremer
Andrew A
AA
Stanhope
Kimber L
KL
Butler
Madeline
M
Booten
Sheri L
SL
Graham
James L
JL
McKay
Robert A
RA
Murray
Susan F
SF
Watts
Lynnetta M
LM
Monia
Brett P
BP
Bhanot
Sanjay
S
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D008252:Macaca fascicularis; D009765:Obesity / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052242:Adiponectin; D001786:Blood Glucose; D016376:Oligonucleotides, Antisense; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1