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
Department of Diabetes, Clinical Sciences Centre, University Hospital Aintree, Liverpool, L9 7AL, UK.
Am J Physiol Endocrinol Metab. 2009 May;296(5):E1042-8. doi: 10.1152/ajpendo.90811.2008. Epub 2009 Feb 3.
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.
我们之前证明，在健康年轻男性中，5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）可刺激人体肌肉对2-脱氧葡萄糖（2DG）的摄取，此时肌肉中AMP激活的蛋白激酶（AMPK）未被检测到激活，但细胞外调节激酶1/2（ERK1/2）被激活。我们测试了AICAR是否能刺激患有或未患有2型糖尿病（T2D）的健康老年患者的肌肉对2DG的摄取。六名健康年轻受试者（23±3岁，体重指数25±2kg/m²；均值±标准误）、八名老年受试者（59±4岁，体重指数28±2kg/m²）和八名T2D患者（62±4岁，体重指数27±2kg/m²）接受了6小时的2DG输注（初始剂量10mg/kg，6mg·kg⁻¹·h⁻¹），并在3至6小时期间接受AICAR（10或20mg·kg⁻¹·h⁻¹）。在0、3和6小时采集股四头肌活检样本。我们测定了：1）2DG摄取；2）总AMPKα活性、AMPK、乙酰辅酶A羧化酶（ACC）和AS160磷酸化水平；3）ERK1/2磷酸化水平。每小时每千克10mg的AICAR使年轻男性的2DG摄取增加2.9±0.7倍（P<0.001），老年男性增加1.8±0.2倍（P<0.01），T2D男性增加1.6±0.1倍；每小时每千克20mg的AICAR使老年男性增加2.5±0.1倍（P<0.001），T2D男性增加2.2±0.2倍（P<0.001）。在3小时时，AMPK活性以及AMPK、ACC和AS160的磷酸化水平均未改变，但两种剂量的AICAR均使ERK1/2磷酸化水平升高。ERK1/2磷酸化水平的倍数变化与2DG摄取密切相关（R² = 0.55，P = 0.003）。AICAR刺激T2D患者肌肉对2DG的摄取程度与年龄匹配的健康对照相同，但存在与年龄相关的减少。
