Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status.
We demonstrated previously that, in healthy young men, 5-aminoimidazole-4-carboxamide 1-beta-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 AMPKalpha 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.
Babraj
John Andree
JA
Department of Diabetes, Clinical Sciences Centre, University Hospital Aintree, Liverpool, L9 7AL, UK.
Mustard
Kristy
K
Sutherland
Calum
C
Towler
Mhari C
MC
Chen
Shaui
S
Smith
Kenneth
K
Green
Kevin
K
Leese
Graham
G
Hardie
David Grahame
DG
Rennie
Michael J
MJ
Cuthbertson
Daniel James
DJ
D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000367:Age Factors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D001706:Biopsy; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003847:Deoxyglucose / Q000097:blood / Q000493:pharmacokinetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D055815:Young Adult
D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D012265:Ribonucleotides; C518767:TBC1D4 protein, human; D000620:Aminoimidazole Carboxamide; D003847:Deoxyglucose; D011494:Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide