title: Treatment with a novel agent combining docosahexaenoate and metformin increases protectin DX and IL-6 production in skeletal muscle and reduces insulin resistance in obese diabetic db/db mice.
abstract: To compare the therapeutic potential of TP-113, a unique molecular entity linking DHA with metformin, for alleviating insulin resistance in obese diabetic mice through the PDX/IL-6 pathway.
  
  
  
  We utilized the generically obese diabetic db/db mouse model for all experiments. Initial studies investigated both a dose and time course response. These results were then utilized to design a long-term (5 week) treatment protocol. Mice were gavaged twice daily with 1 of 3 treatments: 200 mg/kg BW TP113, an equivalent dose of metformin alone (70 mg/kg BW) or water. Whole-body insulin sensitivity was measured using the hyperinsulinaemic-isoglycaemic clamp procedure in awake unrestrained mice.
  
  
  
  We first confirmed that acute TP-113 treatment raises PDX and IL-6 levels in skeletal muscle. We next tested the long-term glucoregulatory effect of oral TP-113 in obese diabetic db/db mice and compared its effect to an equivalent dose of metformin. A 5-week oral treatment with TP-113 reduced insulin resistance compared to both vehicle treatment and metformin alone, revealed by the determination of whole-body insulin sensitivity for glucose disposal using the clamp technique. This insulin-sensitizing effect was explained primarily by improvement of insulin action to suppress hepatic glucose production in TP-113-treated mice. These effects of TP-113 were greater than that of an equivalent dose of metformin, indicating that TP-113 increases metformin efficacy for reducing insulin resistance.
  
  
  
  We conclude that TP-113 improves insulin sensitivity in obese diabetic mice through activation of the PDX/IL-6 signaling axis in skeletal muscle and improved glucoregulatory action in the liver.
authors: Axe Cardiologie Quebec Heart and Lung Research Institute, Laval University, Québec, Canada.|Institute for Nutrition and Functional Foods, Laval University, Québec, Canada.
authors: Patricia L
authors: PL
authors: Mitchell
authors: Axe Cardiologie Quebec Heart and Lung Research Institute, Laval University, Québec, Canada.|Institute for Nutrition and Functional Foods, Laval University, Québec, Canada.
authors: Renato
authors: R
authors: Nachbar
authors: Axe Cardiologie Quebec Heart and Lung Research Institute, Laval University, Québec, Canada.
authors: Dominic
authors: D
authors: Lachance
authors: Axe Cardiologie Quebec Heart and Lung Research Institute, Laval University, Québec, Canada.|Institute for Nutrition and Functional Foods, Laval University, Québec, Canada.
authors: Philippe
authors: P
authors: St-Pierre
authors: Faculté de pharmacie Laboratory of Molecular Pharmacology - CHU de Québec, Laval University, Québec, Canada.
authors: Jocelyn
authors: J
authors: Trottier
authors: Faculté de pharmacie Laboratory of Molecular Pharmacology - CHU de Québec, Laval University, Québec, Canada.
authors: Olivier
authors: O
authors: Barbier
authors: Axe Cardiologie Quebec Heart and Lung Research Institute, Laval University, Québec, Canada.|Institute for Nutrition and Functional Foods, Laval University, Québec, Canada.
authors: André
authors: A
authors: Marette
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology*; D004338:Drug Combinations; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005971:Glutamates / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*
chemical_list: C000591716:10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid; D001786:Blood Glucose; D004338:Drug Combinations; D005971:Glutamates; D007004:Hypoglycemic Agents; D015850:Interleukin-6; C000624431:TP-113; C577686:interleukin-6, mouse; D004281:Docosahexaenoic Acids; D008687:Metformin; D005947:Glucose
keywords: insulin resistance; lipid mediators; omega-3 metabolites