title: Disclosing caffeine action on insulin sensitivity: effects on rat skeletal muscle.
abstract: Caffeine, a non-selective adenosine antagonist, has distinct effects on insulin sensitivity when applied acutely or chronically. Herein, we investigated the involvement of adenosine receptors on insulin resistance induced by single-dose caffeine administration. Additionally, the mechanism behind adenosine receptor-mediated caffeine effects in skeletal muscle was assessed. The effect of the administration of caffeine, 8-cycle-1,3-dipropylxanthine (DPCPX, A1 antagonist), 2-(2-Furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261, A2A antagonist) and 8-(4-{[(4-cyanophenyl)carbamoylmethyl]-oxy}phenyl)-1,3-di(n-propyl)xanthine (MRS1754, A2B antagonist) on whole-body insulin sensitivity was tested. Skeletal muscle Glut4,5'-AMP activated protein kinase (AMPK) and adenosine receptor protein expression were also assessed. The effect of A1 and A2B adenosine agonists on skeletal muscle glucose uptake was evaluated in vitro. Sodium nitroprussiate (SNP, 10nM), a nitric oxide (NO) donor, was used to evaluate the effect of NO on insulin resistance induced by adenosine antagonists. Acute caffeine decreased insulin sensitivity in a concentration dependent manner (Emax=55.54±5.37%, IC50=11.61nM), an effect that was mediated by A1 and A2B adenosine receptors. Additionally, acute caffeine administration significantly decreased Glut4, but not AMPK expression, in skeletal muscle. We found that A1, but not A2B agonists increased glucose uptake in skeletal muscle. SNP partially reversed DPCPX and MRS1754 induced-insulin resistance. Our results suggest that insulin resistance induced by acute caffeine administration is mediated by A1 and A2B adenosine receptors. Both Glut4 and NO seem to be downstream effectors involved in insulin resistance induced by acute caffeine.
authors: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
authors: Joana F
authors: JF
authors: Sacramento
authors: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
authors: Maria J
authors: MJ
authors: Ribeiro
authors: Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, CSIC, Ciber de Enfermedades Respiratorias, CIBERES, Instituto de Salud Carlos III, 47005 Valladolid, Spain.
authors: Sara
authors: S
authors: Yubero
authors: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
authors: Bernardete F
authors: BF
authors: Melo
authors: Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, CSIC, Ciber de Enfermedades Respiratorias, CIBERES, Instituto de Salud Carlos III, 47005 Valladolid, Spain.
authors: Ana
authors: A
authors: Obeso
authors: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal; UIS - Unidade de Investigação em Saúde, Escola Superior de Saúde de Leiria, Instituto Politécnico de Leiria, Campus 2, Morro do Lena, Alto do Vieiro, Apartado 4137, 2411-901 Leiria, Portugal.
authors: Maria P
authors: MP
authors: Guarino
authors: Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, CSIC, Ciber de Enfermedades Respiratorias, CIBERES, Instituto de Salud Carlos III, 47005 Valladolid, Spain.
authors: Constancio
authors: C
authors: Gonzalez
authors: CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal. Electronic address: silvia.conde@fcm.unl.pt.
authors: Silvia V
authors: SV
authors: Conde
mesh_terms: D000818:Animals; D002110:Caffeine / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism
chemical_list: D018047:Receptors, Purinergic P1; D002110:Caffeine
keywords: Adenosine receptors; Caffeine; Glut4; Insulin resistance; Nitric oxide