Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status

• Published in: American journal of physiology: endocrinology and metabolism Vol. 296; no. 5; pp. E1042 - E1048
• Main Authors: Babraj, John Andree, Mustard, Kristy, Sutherland, Calum, Towler, Mhari C, Chen, Shaui, Smith, Kenneth, Green, Kevin, Leese, Graham, Hardie, David Grahame, Rennie, Michael J, Cuthbertson, Daniel James
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2009
• Subjects: Acetyl-CoA Carboxylase - metabolism; Age Factors; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Biopsy; Blood Glucose - drug effects; Blood Glucose - metabolism; Deoxyglucose - blood; Deoxyglucose - pharmacokinetics; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Glucose; GTPase-Activating Proteins - metabolism; Humans; Hypoglycemic Agents - pharmacology; Insulin - blood; Kinases; Male; Mens health; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Musculoskeletal system; Phosphorylation; Protein folding; Protein Kinases - metabolism; Ribonucleotides - pharmacology; Young Adult
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.90811.2008

1 Department of Translational Biomedicine, Heriot Watt University, Edinburgh; 2 Division of Molecular Physiology, College of Life Sciences; 3 Department of Pharmacology and Neurosciences, University of Dundee; 4 Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee; 5 School of Biomedical Sciences, Graduate Entry Medical School, University of Nottingham, Derby City Hospital, Derby; 6 Department of Diabetes, Ninewells Hospital and Medical School, Dundee; and 7 Department of Diabetes, Clinical Sciences Centre, University Hospital Aintree, Liverpool Submitted 1 October 2008 ; accepted in final form 22 January 2009 We demonstrated previously that, in healthy young men, 5-aminoimidazole-4-carboxamide 1-β- D -ribofuranoside (AICAR) stimulates human muscle 2-deoxyglucose (2DG) uptake without detectable activation of muscle AMP-activated protein kinase (AMPK) but with extracellular-regulated kinase 1/2 (ERK1/2) activation. We tested whether AICAR stimulates muscle 2DG uptake in healthy older patients with or without type 2 diabetes (T2D). Six healthy young subjects (23 ± 3 yr, BMI 25 ± 2 kg/m –2 ; means ± SE), eight older subjects (59 ± 4 yr, BMI 28 ± 2 kg/m –2 ), and eight subjects with T2D (62 ± 4 yr, BMI 27 ± 2 kg/m –2 ) received a 6-h 2DG infusion (prime 10 mg/kg, 6 mg·kg –1 ·h –1 ) and AICAR (10 or 20 mg·kg –1 ·h –1 ) from 3 to 6 h. Quadriceps biopsies were taken at 0, 3, and 6 h. We determined 1 ) 2DG uptake, 2 ) total AMPK activity, AMPK, acetyl-CoA carboxylase (ACC), and AS160 phosphorylation, and 3 ) ERK1/2 phosphorylation. Ten milligrams per kilogram per hour AICAR increased 2DG uptake by 2.9 ± 0.7-fold in young men ( P < 0.001), 1.8 ± 0.2-fold in older men ( P < 0.01), and 1.6 ± 0.1-fold in men with T2D; 20 mg·kg –1 ·h –1 AICAR increases were 2.5 ± 0.1-fold (older men, P < 0.001) and 2.2 ± 0.2-fold (men with T2D, P < 0.001). At 3-h AMPK activity and AMPK, ACC and AS160 phosphorylation were unchanged, but ERK1/2 phosphorylation increased at both AICAR doses. The fold changes of ERK1/2 phosphorylation and 2DG uptake closely correlated ( R 2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy age-matched controls, but there is an age-related reduction. 5-aminoimidazole-4-carboxamide-1-β- D -ribofuranoside; adenosine 5'-monophosphate-activated protein kinase; extracellular-signal-regulated kinase 1/2 Address for reprint requests and other correspondence: D. Cuthbertson, Dept. of Diabetes, Clinical Sciences Centre, Univ. Hospital Aintree, Liverpool, L9 7AL, UK (e-mail: daniel.cuthbertson{at}liverpool.ac.uk )