title: Chronic treatment with the AMP-kinase activator AICAR increases glycogen storage and fatty acid oxidation in skeletal muscles but does not reduce hyperglucagonemia and hyperglycemia in insulin deficient rats.
abstract: This study tested whether the glycogen-accumulating effect of chronic in vivo pharmacological 5'AMP-activated protein kinase (AMPK) activation could improve glycemic control under conditions of insulin deficiency. Male Wistar rats were rendered diabetic through the administration of streptozotocin (STZ) and then treated for 7 consecutive days with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Subsequently, glycogen content and synthesis, glucose oxidation, and fatty acid oxidation (FAO) were determined in oxidative and glycolytic skeletal muscles. Glycemia, insulinemia, glucagonemia, and circulating triglycerides (TG) and non-esterified fatty acids (NEFAs) were measured after AICAR treatment. Insulin was almost undetectable in STZ rats and these animals were severely hyperglycemic. Glycogen content was markedly low mainly in glycolytic muscles of STZ rats and AICAR treatment restored it to control values. No differences were found among all muscles studied with regards to the content and phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3. Even though glycogen synthase content was reduced in all muscles from STZ rats, insulin-induced dephosphorylation/activation of this enzyme was preserved and unaffected by AICAR treatment. Glucagon and NEFAS were 2- and 7.4-fold fold higher in STZ rats than controls, respectively. AICAR did not affect hyperglycemia and hyperglucagonemia in STZ rats; however, it normalized circulating NEFAs and significantly increased FAO in glycolytic muscles. In conclusion, even though AICAR-induced AMPK activation enhanced glycogen accumulation in glycolytic muscles and normalized circulating NEFAs and TG levels, the hyperglycemic effects of glucagon likely offset the potentially glucose-lowering effects of AICAR, resulting in no improvement of glycemic control in insulin-deficient rats.
authors.affiliation: Muscle Health Research Center - School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors.forename: Kaio F
authors.initials: KF
authors.lastname: Vitzel
authors.forename: George
authors.initials: G
authors.lastname: Bikopoulos
authors.forename: Steven
authors.initials: S
authors.lastname: Hung
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Pistor
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Patterson
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Rolando B
authors.initials: RB
authors.lastname: Ceddia
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D050154:Adiposity / Q000187:drug effects; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005934:Glucagon / Q000097:blood*; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007328:Insulin / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D010168:Palmitates; D012265:Ribonucleotides; D014280:Triglycerides; D000620:Aminoimidazole Carboxamide; D006003:Glycogen; D005934:Glucagon; D006006:Glycogen Synthase; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000263:Adenylate Kinase; C031143:AICA ribonucleotide