PTP1B antisense oligonucleot normalizes blood glucose, an sensitivity in diabetic mice

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes Pl was investigated using an antisense oligonucleotide in ob/ob and the db/db mice. PTP1B antisense oligonucleotide treatment normalcli: ized plasma glucose levels, postprandial glucose excursion, and HbAic. Hyperinsulinemia was also reduced with improved insulin EXI sensitivity. PTP1B protein and mRNA were reduced in liver and fat Sel with no effect in skeletal muscle. Insulin signaling proteins, insulin AS receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regu20 latory subunit p50a, were increased and P13-kinase p85c expresba sion was decreased in liver and fat. These changes in protein Th expression correlated with increased insulin-stimulated protein me kinase B phosphorylation. The expression of liver gluconeogenic (1' enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6bo bisphosphatase was also down-regulated. These findings suggest Ini that PTP1B modulates insulin signaling in liver and fat, and that we therapeutic modalities targeting PTP1 B inhibition may have clinical wi benefit in type 2 diabetes. sei pri