title: Free fatty acid induced impairment of insulin signaling is prevented by the diastereomeric mixture of calophyllic acid and isocalophyllic acid in skeletal muscle cells.
abstract: Elevated fatty acid levels play a pathogenic role in the development of insulin resistance, associated with type 2 diabetes. Interventions with ability to ameliorate fatty acid-induced insulin resistance might be useful for the management of diabetes. Here, we explored the effect of the diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) on palmitate-induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin-stimulated glucose uptake and translocation of GLUT4 to cell surface. Addition of F015 strongly prevented these inhibitions. Furthermore, F015 effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of IRS-1, AKT and GSK-3β in L6 myotubes. F015 presented a strong inhibition on palmitate-induced production of reactive oxygen species and associated inflammation, as the activation JNK, ERK1/2 and p38 MAPK were greatly reduced. F015 also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in presence of palmitate, resulted in enhanced insulin sensitivity. Results suggest that F015 inhibits palmitate-induced, reactive oxygen species-associated MAPK kinase activation and restored insulin sensitivity through regulating IRS-1 function. All these indicate F015 to be a potentially therapeutic candidate for insulin resistance and type 2 diabetes.
authors.affiliation: Division of Biochemistry, CSIR - Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Natasha
authors.initials: N
authors.lastname: Jaiswal
authors.affiliation: Medicinal and Process Chemistry Division, CSIR - Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Gunaganti
authors.affiliation: Division of Biochemistry, CSIR - Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Chandan Kumar
authors.initials: CK
authors.lastname: Maurya
authors.affiliation: Medicinal and Process Chemistry Division, CSIR - Central Drug Research Institute, Lucknow 226031, India. Electronic address: t_narendra@cdri.res.in.
authors.forename: Tadigoppula
authors.initials: T
authors.lastname: Narender
authors.affiliation: Division of Biochemistry, CSIR - Central Drug Research Institute, Lucknow 226031, India. Electronic address: akhilesh_tamrakar@cdri.res.in.
authors.forename: Akhilesh Kumar
authors.initials: AK
authors.lastname: Tamrakar
mesh_terms: D000818:Animals; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects*; D025461:Feedback, Physiological / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010168:Palmitates / Q000009:adverse effects; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D002867:Chromones; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010168:Palmitates; D017382:Reactive Oxygen Species; C580626:calophyllic acid; D038341:Glycogen Synthase Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Calophyllum inophyllum; Diabetes; Glucose uptake; Inflammation; Insulin resistance