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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
Author(s) -
Mitchell Patricia L.,
Nachbar Renato,
Lachance Dominic,
StPierre Philippe,
Trottier Jocelyn,
Barbier Olivier,
Marette André
Publication year - 2017
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12818
Subject(s) - metformin , insulin resistance , medicine , endocrinology , insulin , skeletal muscle , diabetes mellitus , glucose clamp technique , glucose uptake , type 2 diabetes , pancreatic hormone
Aims 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. Material and methods 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. Results 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. Conclusion 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.