Safranal, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves glucose tolerance in diabetic KK‐Aʸ mice

• Published in: Molecular nutrition & food research Vol. 58; no. 6; pp. 1177 - 1189
• Main Authors: Maeda, Ayumi, Kai, Kenji, Ishii, Megumi, Ishii, Takeshi, Akagawa, Mitsugu
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag GmbH & Co. KGaA 01.06.2014; Blackwell Publishing Ltd; Wiley
• Subjects: Animals; Biological and medical sciences; Crocus - chemistry; Crocus sativus; Cyclohexenes - pharmacology; dephosphorylation; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Feeding. Feeding behavior; Female; functional foods; Fundamental and applied biological sciences. Psychology; glucose; Glucose Intolerance; glucose tolerance; glucose transporters; glycemic effect; Hypoglycemic Agents - pharmacology; insulin; insulin receptors; Insulin Resistance; Male; Medical sciences; Mice; Mice, Inbred Strains; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Myoblasts - drug effects; Myoblasts - metabolism; noninsulin-dependent diabetes mellitus; odor compounds; oral administration; pathogenesis; Plant Extracts - pharmacology; Protein tyrosine phosphatase 1B; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; protein-tyrosine-phosphatase; saffron; Saffron (Crocus sativus L.); Safranal; Signal Transduction; Terpenes - pharmacology; thiols; traditional medicine; tyrosine; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Endocrinopathy; Monocotyledones; Crocus sativus; Phosphoric monoester hydrolases; Esterases; Glucose; Signal transduction; Safranal; Angiospermae; Carbohydrate; Saffron; Iridaceae; Nutrition; Enzyme; Diabetes mellitus; Rodentia; Tolerance; Myotube; Insulin; Vertebrata; Saffron (Crocus sativus L.); Mammalia; Mouse; Animal; Protein tyrosine phosphatase 1B; Hydrolases; Insulin resistance; Spermatophyta; Inhibitor; EC 3.1.3.48; Diabetes; Protein-tyrosine-phosphatase
• ISSN: 1613-4125; 1613-4133; 1613-4133
• DOI: 10.1002/mnfr.201300675

SCOPE: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and its increased activity and expression is implicated in the pathogenesis of insulin resistance. Hence, PTP1B inhibition is anticipated to improve insulin resistance in type 2 diabetic subjects. The aim of this study was to find a novel PTP1B inhibitor from medicinal food and to evaluate its antidiabetic effects. METHODS AND RESULTS: We found that saffron (Crocus sativus L.), which is used both as a spice and as a traditional medicine, potently inhibits PTP1B activity. Analyses of saffron extracts demonstrated that safranal, the saffron's aroma compound, is a principal PTP1B inhibitor, and induces a ligand‐independent activation of insulin signaling in cultured myotubes. Our data implied that the molecular mechanism underlying the inactivation of PTP1B could be attributed to the covalent modification of the catalytic cysteinyl thiol by safranal through a Michael addition. Furthermore, safranal significantly enhanced glucose uptake through the translocation of glucose transporter 4. We also demonstrated that 2‐wk oral administration of 20 mg/kg/day safranal improved impaired glucose tolerance in type 2 diabetic KK‐Aʸ mice. CONCLUSION: Our results strongly suggest the usefulness of safranal in antidiabetic treatment for type 2 diabetic subjects.