title: Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance.
abstract: The important pathological consequences of insulin resistance arise from the detrimental effects of accumulated long-chain fatty acids and their respective acylcarnitines. The aim of this study was to test whether exercise combined with decreasing the content of long-chain acylcarnitines represents an effective strategy to improve insulin sensitivity in diabetes. We used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB), treatment and exercise to decrease acylcarnitine contents in the plasma and muscles in the insulin resistance models of high fat diet (HFD) fed C57BL/6 mice and db/db mice. The methyl-GBB treatment induced a substantial decrease in all acylcarnitine concentrations in both fed and fasted states as well as when it was combined with exercise. In the HFD fed mice methyl-GBB treatment improved both glucose and insulin tolerance. Methyl-GBB administration, exercise and the combination of both improved insulin sensitivity and reduced blood glucose levels in db/db mice. Methyl-GBB administration and the combination of the drug and exercise activated the PPARα/PGC1α signaling pathway and stimulated the corresponding target gene expression. Insulin insensitivity in db/db mice was not induced by significantly increased fatty acid metabolism, while increased insulin sensitivity by both treatments was not related to decreased fatty acid metabolism in muscles. The pharmacologically reduced long-chain acylcarnitine content represents an effective strategy to improve insulin sensitivity. The methyl-GBB treatment and lifestyle changes via increased physical activity for one hour a day have additive insulin sensitizing effects in db/db mice.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia. Electronic address: ledgars@biomed.lu.lv.
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str 16, Riga LV1007, Latvia.
authors.forename: Marina
authors.initials: M
authors.lastname: Makrecka-Kuka
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia.
authors.forename: Elina
authors.initials: E
authors.lastname: Makarova
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Volska
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia.
authors.forename: Baiba
authors.initials: B
authors.lastname: Svalbe
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia.
authors.forename: Eduards
authors.initials: E
authors.lastname: Sevostjanovs
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia.
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia.
authors.forename: Janis
authors.initials: J
authors.lastname: Kuka
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga LV1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str 16, Riga LV1007, Latvia.
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D047493:PPAR alpha; D000644:Quaternary Ammonium Compounds; C116917:acylcarnitine; C000602882:methyl-gamma-butyrobetaine; D005680:gamma-Aminobutyric Acid; D005947:Glucose; D002331:Carnitine
keywords: Acylcarnitine; Diabetes; Energy metabolism; Exercise; Fatty acid oxidation; Novel treatment