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Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase
Stephanie M Stanford1,2, Alexander E Aleshin3, Vida Zhang1,2
1Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Abstract:
Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.
Insights
Low-molecular-weight protein tyrosine phosphatase (LMPTP) promotes insulin resistance. Inhibiting LMPTP in mice protected against diet-induced diabetes, suggesting LMPTP inhibitors could treat type 2 diabetes.
Area of Science:
- Biochemistry
- Metabolic diseases
- Pharmacology
Background:
- Insulin resistance, a hallmark of type 2 diabetes, is linked to obesity.
- Tyrosine phosphatases dephosphorylate the insulin receptor (IR), making them potential therapeutic targets.
- The role of low-molecular-weight protein tyrosine phosphatase (LMPTP) in insulin signaling in vivo remains unclear.
Purpose of the Study:
- To investigate the in vivo role of LMPTP in insulin signaling and diet-induced diabetes.
- To develop and evaluate a selective small-molecule inhibitor of LMPTP.
Main Methods:
- Generated global and liver-specific LMPTP knockout mice.
- Administered a high-fat diet to induce diabetes.
- Developed and tested an orally bioavailable, selective LMPTP inhibitor.
Main Results:
- LMPTP deletion protected mice from high-fat diet-induced diabetes without altering body weight.
- The novel LMPTP inhibitor increased liver insulin receptor phosphorylation in vivo.
- LMPTP inhibition reversed diet-induced diabetes in mice.
Conclusions:
- LMPTP is a key contributor to insulin resistance.
- Targeting LMPTP with small-molecule inhibitors represents a promising therapeutic strategy for type 2 diabetes.
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