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

TY - JOUR

T1 - Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status

AU - Babraj, John Andree

AU - Mustard, Kirsty

AU - Sutherland, Calum

AU - Towler, Mhari C.

AU - Chen, Shaui

AU - Smith, Kenneth

AU - Green, Kevin

AU - Leese, Graham

AU - Hardie, David Grahame

AU - Rennie, Michael J.

AU - Cuthbertson, Daniel James

PY - 2009/5

Y1 - 2009/5

N2 - Babraj JA, Mustard K, Sutherland C, Towler MC, Chen S, Smith K, Green K, Leese GP, Hardie DG, Rennie MJ, Cuthbertson DJ. Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status. Am J Physiol Endocrinol Metab 296: E1042-E1048, 2009. First published February 3, 2009; doi: 10.1152/ajpendo.90811.2008.-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 AMPK alpha 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.

AB - Babraj JA, Mustard K, Sutherland C, Towler MC, Chen S, Smith K, Green K, Leese GP, Hardie DG, Rennie MJ, Cuthbertson DJ. Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status. Am J Physiol Endocrinol Metab 296: E1042-E1048, 2009. First published February 3, 2009; doi: 10.1152/ajpendo.90811.2008.-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 AMPK alpha 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.

KW - 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside

KW - adenosine

KW - 5 '-monophosphate-activated protein kinase

KW - extracellular-signal-regulated kinase 1/2

KW - INSULIN-RESISTANCE

KW - ACUTE EXERCISE

KW - HEALTHY-MEN

KW - WHOLE-BODY

KW - ACTIVATION

KW - TRANSPORT

KW - AMPK

KW - PATHWAY

KW - PHOSPHORYLATION

KW - RIBOSIDE

U2 - 10.1152/ajpendo.90811.2008

DO - 10.1152/ajpendo.90811.2008

M3 - Article

C2 - 19190259

SN - 0193-1849

VL - 296

SP - E1042-E1048

JO - AJP - Endocrinology and Metabolism (Endocrinology and Metabolism

JF - AJP - Endocrinology and Metabolism (Endocrinology and Metabolism

IS - 5

ER -