title: Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.
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.
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Aleshin
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Vida
authors.initials: V
authors.lastname: Zhang
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hedrick
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zou
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Santhi R
authors.initials: SR
authors.lastname: Ganji
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Bliss
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Fusayo
authors.initials: F
authors.lastname: Yamamoto
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Bobkov
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Janna
authors.initials: J
authors.lastname: Kiselar
authors.affiliation: Institute for Genetic Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Yingge
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Cadwell
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Khare
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Barquilla
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Thomas D Y
authors.identifier: 0000-0003-4856-6233
authors.initials: TDY
authors.lastname: Chung
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.affiliation: Department of Orthopaedic Surgery and Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Bankston
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Liddington
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
mesh_terms: D000818:Animals; D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D017353:Gene Deletion; D020128:Inhibitory Concentration 50; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D015394:Molecular Structure; D008970:Molecular Weight; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D054852:Small Molecule Libraries / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D017027:Protein Tyrosine Phosphatases