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Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.
Stanford SM1,2, Aleshin AE3, Zhang V1,2, Ardecky RJ4, Hedrick MP4, Zou J4, Ganji SR4, Bliss MR1, Yamamoto F4, Bobkov AA4, Kiselar J5, Liu Y6, Cadwell GW3, Khare S4, Yu J4, Barquilla A1, Chung TDY4, Mustelin T7, Schenk S8, Bankston LA3, Liddington RC3, Pinkerton AB4, Bottini N1,2.
Author information
- 1 Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
- 2 Department of Medicine, University of California, San Diego, La Jolla, California, USA.
- 3 Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
- 4 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
- 5 Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.
- 6 Institute for Genetic Medicine, University of Southern California, Los Angeles, California, USA.
- 7 Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.
- 8 Department of Orthopaedic Surgery and Department of Pediatrics, University of California, San Diego, 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.
Comment in
- Metabolic Disease: Protein tyrosine phosphatase inhibitor reverses diabetes. [Nat Rev Drug Discov. 2017]
- Diabetes: LMPTP inhibitors - potential treatment for type 2 diabetes? [Nat Rev Endocrinol. 2017]
- PMID: 28346406
- PMCID: PMC5435566
- DOI: 10.1038/nchembio.2344
