Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase

Nat Chem Biol. 2017 Jun;13(6):624-632. doi: 10.1038/nchembio.2344. Epub 2017 Mar 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / genetics
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use*
  • Gene Deletion
  • Inhibitory Concentration 50
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Models, Biological
  • Molecular Structure
  • Molecular Weight
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / genetics*
  • Small Molecule Libraries* / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Protein Tyrosine Phosphatases

Associated data

  • PubChem-Substance/329891385
  • PubChem-Substance/329891396
  • PubChem-Substance/329891406
  • PubChem-Substance/329891407
  • PubChem-Substance/329891408
  • PubChem-Substance/329891409
  • PubChem-Substance/329891410
  • PubChem-Substance/329891411
  • PubChem-Substance/329891412
  • PubChem-Substance/329891386
  • PubChem-Substance/329891387
  • PubChem-Substance/329891388
  • PubChem-Substance/329891389
  • PubChem-Substance/329891390
  • PubChem-Substance/329891391
  • PubChem-Substance/329891392
  • PubChem-Substance/329891393
  • PubChem-Substance/329891394
  • PubChem-Substance/329891395
  • PubChem-Substance/329891397
  • PubChem-Substance/329891398
  • PubChem-Substance/329891399
  • PubChem-Substance/329891400
  • PubChem-Substance/329891401
  • PubChem-Substance/329891402
  • PubChem-Substance/329891403
  • PubChem-Substance/329891404
  • PubChem-Substance/329891405