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 ob͞ob and db͞db 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 p50␣, were increased and PI3-kinase p85␣ 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.

Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation

“…Antisense oligonucleotides that lower PTP1B levels only in adipose tissue and liver reduce diet-induced obesity and enhance insulin signaling in obese (ob/ob) and diabetic (db/db) mice (48,49). Similarly, administration of PTP1B antisense oligonucleotides to monkeys reduces PTP1B in adipose tissue and liver and improves insulin sensitivity (50).…”

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

“…Moreover, studies with obese rats have shown that expression of leucocyte common antigen-related protein tyrosine phosphatase in liver is downregulated after TNFα blockade [41], and in rat hepatoma cells TNFα increased SHIP2 production. Overactivation of phosphatases is one way in which insulin signalling becomes blocked, and PTPN1, which dephosphorylates the activated insulin receptors and their substrates, has been shown to play a major role in both insulin resistance and type 2 diabetes [42,43]. We therefore decided to check whether lack of PTPN1 in brown adipocytes might confer protection against TNFα-induced insulin resistance.…”

Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling

“…Expression of wildtype PTP1B did not significantly alter the dose response to BDNF at the 5 min BDNF time point (Fig. 1D), PTP1B Inhibition or Genetic PTP1B Deficiency Enhances BDNF/TrkB Signaling-Inhibition of PTP1B activity sensitizes the leptin-and insulin-signaling pathways in vitro and in vivo (35)(36)(37). To investigate whether acute inhibition of PTP1B activity similarly enhances BDNF/TrkB signaling, SH-SY5Y-TrkB cells were pretreated with a cell permeable PTP1B-specific inhibitor (compound II, 100 nM for 5 min (33)) or vehicle prior to either vehicle or BDNF stimulation.…”