Longnus S L, Ségalen C, Giudicelli J, Sajan M P, Farese R V, Van Obberghen E
INSERM U145, IFR 50, Faculty of Medicine, Avenue de Valombrose, 06107,, Nice Cedex 2, France.
Diabetologia. 2005 Dec;48(12):2591-601. doi: 10.1007/s00125-005-0016-3. Epub 2005 Nov 11.
AIMS/HYPOTHESIS: 5'AMP-activated protein kinase (AMPK) and insulin stimulate glucose transport in heart and muscle. AMPK acts in an additive manner with insulin to increase glucose uptake, thereby suggesting that AMPK activation may be a useful strategy for ameliorating glucose uptake, especially in cases of insulin resistance. In order to characterise interactions between the insulin- and AMPK-signalling pathways, we investigated the effects of AMPK activation on insulin signalling in the rat heart in vivo.
Male rats (350-400 g) were injected with 1 g/kg 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) or 250 mg/kg metformin in order to activate AMPK. Rats were administered insulin 30 min later and after another 30 min their hearts were removed. The activities and phosphorylation levels of components of the insulin-signalling pathway were subsequently analysed in individual rat hearts.
AICAR and metformin administration activated AMPK and enhanced insulin signalling downstream of protein kinase B in rat hearts in vivo. Insulin-induced phosphorylation of glycogen synthase kinase 3 (GSK3) beta, p70 S6 kinase (p70S6K)(Thr389) and IRS1(Ser636/639) were significantly increased following AMPK activation. To the best of our knowledge, this is the first report of heightened insulin responses of GSK3beta and p70S6K following AMPK activation. In addition, we found that AMPK inhibits insulin stimulation of IRS1-associated phosphatidylinositol 3-kinase activity, and that AMPK activates atypical protein kinase C and extracellular signal-regulated kinase in the heart.
CONCLUSIONS/INTERPRETATIONS: Our data are indicative of differential effects of AMPK on the activation of components in the cardiac insulin-signalling pathway. These intriguing observations are critical for characterisation of the crosstalk between AMPK and insulin signalling.
目的/假设：5'-AMP激活蛋白激酶（AMPK）和胰岛素可刺激心脏和肌肉中的葡萄糖转运。AMPK与胰岛素以相加的方式作用来增加葡萄糖摄取，因此提示AMPK激活可能是改善葡萄糖摄取的一种有用策略，尤其是在胰岛素抵抗的情况下。为了阐明胰岛素信号通路与AMPK信号通路之间的相互作用，我们在体内研究了AMPK激活对大鼠心脏胰岛素信号的影响。
给雄性大鼠（350 - 400 g）注射1 g/kg的5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）或250 mg/kg的二甲双胍以激活AMPK。30分钟后给大鼠注射胰岛素，再过30分钟后取出它们的心脏。随后在各个大鼠心脏中分析胰岛素信号通路各组分的活性和磷酸化水平。
给予AICAR和二甲双胍可激活AMPK，并增强体内大鼠心脏中蛋白激酶B下游的胰岛素信号。AMPK激活后，胰岛素诱导的糖原合酶激酶3（GSK3）β、p70 S6激酶（p70S6K）（苏氨酸389位点）和胰岛素受体底物1（IRS1）（丝氨酸636/639位点）的磷酸化显著增加。据我们所知，这是首次报道AMPK激活后GSK3β和p70S6K的胰岛素反应增强。此外，我们发现AMPK抑制胰岛素对IRS1相关磷脂酰肌醇3激酶活性的刺激，并且AMPK在心脏中激活非典型蛋白激酶C和细胞外信号调节激酶。
结论/解读：我们的数据表明AMPK对心脏胰岛素信号通路中各组分激活具有不同的作用。这些有趣的观察结果对于阐明AMPK与胰岛素信号之间的相互作用至关重要。
