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

John Andree Babraj, Kristy Mustard, Calum Sutherland, Mhari C. Towler, Shaui Chen, Kenneth Smith, Kevin Green, Graham Leese, David Grahame Hardie, Michael J. Rennie, Daniel James Cuthbertson

Research output: Contribution to journalArticle

Abstract

We demonstrated previously that, in healthy young men, 5-aminoimidazole-4- carboxamide 1-ß-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 AMPKa 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 (R2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy agematched controls, but there is an age-related reduction. Copyright © 2009 the American Physiological Society.

Original languageEnglish
Pages (from-to)E1042-E1048
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume296
Issue number5
DOIs
Publication statusPublished - May 2009

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Deoxyglucose
Type 2 Diabetes Mellitus
Skeletal Muscle
Glucose
Phosphorylation
AMP-Activated Protein Kinases
Phosphotransferases
Acetyl-CoA Carboxylase
Muscles
acadesine
Healthy Volunteers
Biopsy

Keywords

  • 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside
  • Adenosine 5′-monophosphate-activated protein kinase
  • Extracellular-signal-regulated kinase 1/2

Cite this

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. / Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status. In: American Journal of Physiology - Endocrinology and Metabolism. 2009 ; Vol. 296, No. 5. pp. E1042-E1048.
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abstract = "We demonstrated previously that, in healthy young men, 5-aminoimidazole-4- carboxamide 1-{\ss}-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 AMPKa 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 (R2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy agematched controls, but there is an age-related reduction. Copyright {\circledC} 2009 the American Physiological Society.",
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Babraj, JA, Mustard, K, Sutherland, C, Towler, MC, Chen, S, Smith, K, Green, K, Leese, G, Hardie, DG, Rennie, MJ & Cuthbertson, DJ 2009, 'Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status', American Journal of Physiology - Endocrinology and Metabolism, vol. 296, no. 5, pp. E1042-E1048. https://doi.org/10.1152/ajpendo.90811.2008

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

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 296, No. 5, 05.2009, p. E1042-E1048.

Research output: Contribution to journalArticle

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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, Kristy

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

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N2 - We demonstrated previously that, in healthy young men, 5-aminoimidazole-4- carboxamide 1-ß-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 AMPKa 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 (R2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy agematched controls, but there is an age-related reduction. Copyright © 2009 the American Physiological Society.

AB - We demonstrated previously that, in healthy young men, 5-aminoimidazole-4- carboxamide 1-ß-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 AMPKa 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 (R2 = 0.55, P = 0.003). AICAR stimulates muscle 2DG uptake in T2D to the same extent as in healthy agematched controls, but there is an age-related reduction. Copyright © 2009 the American Physiological Society.

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