title: Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle.
abstract: Cancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP-activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process.
  
  
  
  We used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15 mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation.In vitroassays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability.
  
  
  
  The animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR.
  
  
  
  DOX leads to conditions similar to cachexia, with severe glucose intolerance bothin vivoandin vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.
authors.affiliation: Departamento de Biologia Celular e do Desenvolvimento Instituto de Ciências Biomédicas I Avenida Lineu Prestes 1524, Cidade Universitária 05508-900 São Paulo SP Brazil.
authors.forename: Edson Alves
authors.initials: EA
authors.lastname: de Lima Junior
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas Universidade de São Paulo São Paulo SP Brazil.
authors.forename: Alex Shimura
authors.initials: AS
authors.lastname: Yamashita
authors.affiliation: Laboratório de Investigação em Nutrição Clínica e Esportiva(Labince), Faculdade de Nutrição (FANUT) Universidade Federal de Goiás (UFG) Goiânia Goiás Brasil.
authors.forename: Gustavo Duarte
authors.initials: GD
authors.lastname: Pimentel
authors.affiliation: Department of Neurobiology, Physiology and Behavior University of California Davis Davis CA 95616 USA.
authors.forename: Luís G O
authors.initials: LG
authors.lastname: De Sousa
authors.affiliation: Departamento de Biociências UNIFESP São Paulo SP Brasil.
authors.forename: Ronaldo Vagner T
authors.initials: RV
authors.lastname: Santos
authors.affiliation: Laboratório de Fisiopatologia Experimental Universidade do Extremo Sul Catarinense, Av. Universitária, 1105 Criciúma 88806-000 SC Brazil.
authors.forename: Cinara Ludvig
authors.initials: CL
authors.lastname: Gonçalves
authors.affiliation: Laboratório de Fisiopatologia Experimental Universidade do Extremo Sul Catarinense, Av. Universitária, 1105 Criciúma 88806-000 SC Brazil.
authors.forename: Emilio Luiz
authors.initials: EL
authors.lastname: Streck
authors.affiliation: Exercise and Immunometabolism Research Group, Department of Physical Education Universidade Estadual Paulista, UNESP Rua Roberto Simonsen, 305 19060-900 Presidente Prudente São Paulo Brazil.
authors.forename: Fábio Santos
authors.initials: FS
authors.lastname: de Lira
authors.affiliation: Departamento de Biologia Celular e do Desenvolvimento Instituto de Ciências Biomédicas I Avenida Lineu Prestes 1524, Cidade Universitária 05508-900 São Paulo SP Brazil.
authors.forename: Jose Cesar
authors.initials: JC
authors.lastname: Rosa Neto
mesh_terms: D000818:Animals; D000855:Anorexia / Q000209:etiology / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D001786:Blood Glucose; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D005215:Fasting; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D055948:Sarcopenia / Q000209:etiology / Q000378:metabolism / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D016207:Cytokines; D004317:Doxorubicin; D005947:Glucose
keywords: AMPk; Anthracycline; Chemotherapy; Doxorubicin; Glucose intolerance; Hyperglycaemia; Skeletal muscle