Back to Search
Start Over
Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice.
- Source :
-
Journal of pharmacological sciences [J Pharmacol Sci] 2018 May; Vol. 137 (1), pp. 38-46. Date of Electronic Publication: 2018 Mar 06. - Publication Year :
- 2018
-
Abstract
- The anti-diabetic and anti-obesity effects of the allosteric protein tyrosine phosphatase 1B (PTP1B) inhibitor 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzoylamide (KY-226) were pharmacologically evaluated. KY-226 inhibited human PTP1B activity (IC <subscript>50</subscript>  = 0.28 μM), but did not exhibit peroxisome proliferator-activated receptor γ (PPARγ) agonist activity. In rodent preadipocytes (3T3-L1), KY-226 up to 10 μM had no effects on adipocyte differentiation, whereas pioglitazone, a PPARγ agonist, markedly promoted it. In human hepatoma-derived cells (HepG2), KY-226 (0.3-10 μM) increased the phosphorylated insulin receptor (pIR) produced by insulin. In db/db mice, the oral administration of KY-226 (10 and 30 mg/kg/day, 4 weeks) significantly reduced plasma glucose and triglyceride levels as well as hemoglobin A1c values without increasing body weight gain, while pioglitazone exerted similar effects with increases in body weight gain. KY-226 attenuated plasma glucose elevations in the oral glucose tolerance test. KY-226 also increased pIR and phosphorylated Akt in the liver and femoral muscle. In high-fat diet-induced obese mice, the oral administration of KY-226 (30 and 60 mg/kg/day, 4 weeks) decreased body weight gain, food consumption, and fat volume gain with increases in phosphorylated STAT3 in the hypothalamus. In conclusion, KY-226 exerted anti-diabetic and anti-obesity effects by enhancing insulin and leptin signaling, respectively.<br /> (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Subjects :
- 3T3 Cells
Adipocytes cytology
Animals
Benzamides therapeutic use
Biphenyl Compounds therapeutic use
Cell Differentiation drug effects
Diabetes Mellitus, Experimental genetics
Dose-Response Relationship, Drug
Enzyme Inhibitors therapeutic use
Hep G2 Cells
Humans
Insulin physiology
Leptin physiology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Molecular Targeted Therapy
Obesity genetics
Phosphorylation
STAT3 Transcription Factor metabolism
Benzamides pharmacology
Biphenyl Compounds pharmacology
Diabetes Mellitus, Experimental drug therapy
Enzyme Inhibitors pharmacology
Insulin metabolism
Leptin metabolism
Obesity drug therapy
Protein Tyrosine Phosphatase, Non-Receptor Type 1 antagonists & inhibitors
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1347-8648
- Volume :
- 137
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of pharmacological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 29731242
- Full Text :
- https://doi.org/10.1016/j.jphs.2018.03.001