title: Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance.
abstract: Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California;
authors.forename: Katherine
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California;
authors.forename: Alice
authors.initials: A
authors.lastname: Jih
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California;
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Kavaler
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California;
authors.forename: William S
authors.initials: WS
authors.lastname: Lagakos
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California;
authors.forename: Dayoung
authors.initials: D
authors.lastname: Oh
authors.affiliation: Metabolon, Durham, North Carolina; and.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Watkins
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California; Rady Children's Hospital of San Diego, San Diego, California janekim@ucsd.edu.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D011236:Prediabetic State / Q000209:etiology / Q000517:prevention & control; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011355:Prodrugs; C000602200:Sal-DHA compound; D012459:Salicylates; D004281:Docosahexaenoic Acids; D052216:Glucagon-Like Peptide 1
keywords: docosahexaenoic acid; insulin-resistance; obesity; salicylate