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PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in
Bradley A Zinker1, Cristina M Rondinone, James M Trevillyan
1Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. bradley.zinker@abbott.com
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.
Insights
Inhibiting protein-tyrosine phosphatase 1B (PTP1B) using antisense oligonucleotides improved glucose control and insulin sensitivity in diabetic mice. This suggests PTP1B is a potential therapeutic target for type 2 diabetes.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Protein-tyrosine phosphatase 1B (PTP1B) is implicated in insulin resistance.
- Dysregulation of PTP1B activity contributes to the pathophysiology of type 2 diabetes.
Purpose of the Study:
- To investigate the therapeutic potential of PTP1B inhibition in a mouse model of type 2 diabetes.
- To elucidate the molecular mechanisms underlying PTP1B's role in insulin signaling and glucose metabolism.
Main Methods:
- Utilized antisense oligonucleotide (ASO) therapy to reduce PTP1B expression in ob/ob and db/db mice.
- Assessed metabolic parameters including plasma glucose, HbA(1C), and insulin sensitivity.
- Analyzed PTP1B expression and insulin signaling pathway components in liver, fat, and skeletal muscle.
Main Results:
- PTP1B ASO treatment normalized glucose levels, reduced HbA(1C), and improved insulin sensitivity.
- Decreased PTP1B expression in liver and fat led to enhanced insulin signaling, including increased Akt phosphorylation.
- Down-regulation of key gluconeogenic enzymes in the liver was observed.
Conclusions:
- PTP1B plays a critical role in modulating insulin signaling in hepatic and adipose tissues.
- Targeting PTP1B with therapeutic agents represents a promising strategy for managing type 2 diabetes.
- Further research into PTP1B inhibitors could yield novel treatments for metabolic disorders.