AMPK和運(yùn)動(dòng)：骨骼肌攝取葡萄糖和胰島素敏感性

1、AMPK和運(yùn)動(dòng)：骨骼肌攝取葡萄糖和胰島素敏感性AMPK是一個(gè)進(jìn)化保守的細(xì)胞能量感受器，在運(yùn)動(dòng)過(guò)程中被激活。激活的AMPK可以增加骨骼肌葡萄糖攝取、脂肪酸氧化、線粒體生物合成和胰島素敏感性，這些過(guò)程在肥胖患者體內(nèi)減弱，從而易引發(fā)胰島素抵抗。運(yùn)動(dòng)促進(jìn)葡萄糖攝取的機(jī)制涉及AMPK，但不明確AMPK是否參與運(yùn)動(dòng)提高胰島素敏感性的過(guò)程。了解這些代謝過(guò)程將為治療肥胖和胰島素抵抗提供新的契機(jī)，故本綜述將討論AMPK如何參與調(diào)節(jié)骨骼肌代謝（葡萄糖的攝取和胰島素敏感性）。AMPK和運(yùn)動(dòng)運(yùn)動(dòng)時(shí)，為了給肌肉收縮提供足夠的能量，骨骼肌中ATP代謝速度增加（>100倍）1。在這種情況下，AMP和ADP濃度迅速增加

2、，而ATP水平只略有下降。AMPK是細(xì)胞能量感受器，能被AMP和ADP激活，與此相一致，嚙類動(dòng)物和人類的骨骼肌中AMPK在運(yùn)動(dòng)過(guò)程中被激活2-5。運(yùn)動(dòng)通過(guò)AMPK介導(dǎo)的胰島素非依賴性機(jī)制調(diào)節(jié)葡萄糖攝取6。重要的是，在2型糖尿病患者的骨骼肌中，運(yùn)動(dòng)調(diào)節(jié)GLUT4轉(zhuǎn)運(yùn)的通路沒(méi)有受損7，并且，運(yùn)動(dòng)可以提高胰島素的敏感性。由于這些原因，運(yùn)動(dòng)通常被建議用于預(yù)防和治療胰島素抵抗。因此，理解運(yùn)動(dòng)調(diào)節(jié)葡萄糖的攝取潛在機(jī)制是一個(gè)重要的研究領(lǐng)域。骨骼肌攝取葡萄糖的調(diào)節(jié)胰島素促進(jìn)骨骼肌攝取葡萄糖 胰島素生物學(xué)效應(yīng)通過(guò)信號(hào)轉(zhuǎn)導(dǎo)而實(shí)現(xiàn)，隨著分子生物學(xué)的發(fā)展，人們對(duì)胰島素信號(hào)轉(zhuǎn)導(dǎo)途徑中的的系列級(jí)聯(lián)反應(yīng)逐步明確。簡(jiǎn)言之，胰

3、島素通過(guò)IRàIRSàPI3KàAkt/PKCx/làAS160信號(hào)通路調(diào)節(jié)GLUT4轉(zhuǎn)運(yùn)到細(xì)胞膜上，從而促進(jìn)葡萄糖的攝取。運(yùn)動(dòng)促進(jìn)骨骼肌攝取葡萄糖 同胰島素，運(yùn)動(dòng)也是通過(guò)調(diào)節(jié)GLUT4轉(zhuǎn)運(yùn)到質(zhì)膜和橫小管，增加骨骼肌葡萄糖攝取。但是，在骨骼肌中，胰島素和運(yùn)動(dòng)/收縮通過(guò)不同的機(jī)制調(diào)節(jié)對(duì)葡萄糖的攝取。此觀點(diǎn)來(lái)自于以下發(fā)現(xiàn)：1）PI3激酶抑制劑渥曼霉素（Wortmannin）抑制胰島素刺激的葡萄糖攝取，但不抑制收縮刺激的葡萄糖攝取。收縮不促進(jìn)IRS-1自身磷酸化或增加PI3激酶的活性8-11。2）基因敲除主要的胰島素信號(hào)蛋白IRS1和AKT2，不影響收縮介導(dǎo)的

4、葡萄糖攝取42-43。3）胰島素與收縮刺激葡萄糖的攝取有疊加作用14-15。4）胰島素抵抗患者和嚙齒動(dòng)物，收縮介導(dǎo)的葡萄糖攝取不受影響16-19。相反，也有研究發(fā)現(xiàn)離體骨骼肌收縮使Akt磷酸化水平上升，并且Goodyear等人報(bào)道，PI3激酶抑制劑Wortmannin和LY294002可抑制收縮引起的Akt活性增加。究竟運(yùn)動(dòng)/骨骼肌收縮是否激活PI3K-Akt還有待進(jìn)一步的研究證實(shí)。慢性運(yùn)動(dòng)訓(xùn)練雖然有研究表明肥胖者體內(nèi)的AMPK活性和蛋白表達(dá)降低，但慢性運(yùn)動(dòng)訓(xùn)練仍能增強(qiáng)AMPK的蛋白表達(dá)和活性30。因此，AMPK可能通過(guò)TBC1D1 和TBC1D4 的磷酸化，增強(qiáng)胰島素的敏感性?；谌祟惡痛笫?/p>

5、的研究都表明，慢性運(yùn)動(dòng)訓(xùn)練增加了TBC1D4 的蛋白表達(dá)和PAS磷酸化，這一結(jié)果支持了上述觀點(diǎn)。正常情況下，肥胖2型糖尿病患者骨骼肌中TBC1D4的磷酸化被削弱，但10周的耐力訓(xùn)練可以使TBC1D4的磷酸化恢復(fù)到非糖尿病患者的水平31。目前尚不知TBC1D1是否有類似的發(fā)現(xiàn)。有趣的是，旨在為肥胖者減重的兩周的飲食干預(yù)改善了胰島素敏感性，卻沒(méi)有影響TBC1D1的磷酸化。而相反研究報(bào)道，飲食干預(yù)的確增加了TBC1D1 Ser231和Ser660，卻沒(méi)有像鍛煉那樣增加Ser700或PAS的磷酸化32。肥胖的2型糖尿病患者的耐力訓(xùn)練和健康男性的耐力訓(xùn)練都導(dǎo)致了AMPK 3表達(dá)減少33。而敲除3亞基則會(huì)

6、損害鍛煉后的糖元合成。一種可能的解釋是，3表達(dá)的減少是一種對(duì)運(yùn)動(dòng)的應(yīng)激反應(yīng)，提高了機(jī)體氧化能力和脂肪氧化，而增加糖原利用率。近期有研究認(rèn)為，考慮到3的表達(dá)減弱，AMPK 活性水平的增加可能是由于與1有關(guān)的復(fù)合物的形成。結(jié)論總之，AMPK在運(yùn)動(dòng)調(diào)節(jié)葡萄糖攝取過(guò)程中起重要作用，并可能參與急性和慢性兩種運(yùn)動(dòng)的胰島素增敏作用。許多研究已經(jīng)提出了一些介導(dǎo)運(yùn)動(dòng)的胰島素增敏作用的可能機(jī)制，但明確定義AMPK在其中的作用需要進(jìn)一步的研究。運(yùn)動(dòng)為健康提供無(wú)限益處，是預(yù)防和治療肥胖誘導(dǎo)的胰島素抵抗最經(jīng)濟(jì)有效的方法之一。因此，未來(lái)關(guān)于運(yùn)動(dòng)的胰島素增敏作用機(jī)制的研究至關(guān)重要，它可以為相關(guān)疾病的藥物和非藥物（如運(yùn)動(dòng)）治

7、療的發(fā)展提供新的策略。參考文獻(xiàn)1 Sahlin K, Tonkonogi M and Soderlund K. Energy supply and muscle fatigue in humansJ. Acta Physiol Scand, 1998, 162:261-266.2 Hayashi T, Hirshman MF, Kurth EJ, Winder WW and Goodyear LJ. Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on

8、glucose transportJ. Diabetes, 1998, 47:1369-1373.3 Hutber CA, Hardie DG and Winder WW. Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinaseJ. Am J Physiol, 1997, 272:E262-266.4 Ihlemann J, Ploug T, Hellsten Y and Galbo H. Effect of tension on co

9、ntraction-induced glucose transport in rat skeletal muscleJ. Am J Physiol, 1999, 277:E208-214.5 Rasmussen BB, Hancock CR and Winder WW. Postexercise recovery of skeletal muscle malonyl-CoA, acetyl-CoA carboxylase, and AMP-activated protein kinaseJ. J Appl Physiol, 1998, 85:1629-1634.6 O'Neill HM

10、, Maarbjerg SJ, Crane JD, Jeppesen J, Jorgensen SB, Schertzer JD, Shyroka O, Kiens B, van Denderen BJ, Tarnopolsky MA, Kemp BE, Richter EA and Steinberg GR. AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and gluc

11、ose uptake during exerciseJ. Proc Natl Acad Sci U S A, 2011, 108:16092-16097.7 Kennedy JW, Hirshman MF, Gervino EV, Ocel JV, Forse RA, Hoenig SJ, Aronson D, Goodyear LJ and Horton ES. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diab

12、etesJ. Diabetes, 1999, 48:1192-1197.8 Yeh JI, Gulve EA, Rameh L and Birnbaum MJ. The effects of wortmannin on rat skeletal muscle. Dissociation of signaling pathways for insulin- and contraction-activated hexose transportJ. J Biol Chem, 1995, 270:2107-2111.9 Meirhaeghe A, Crowley V, Lenaghan C, Lell

13、iott C, Green K, Stewart A, Hart K, Schinner S, Sethi JK, Yeo G, Brand MD, Cortright RN, O'Rahilly S, Montague C and Vidal-Puig AJ. Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivoJ. Biochem J,

14、 2003, 373:155-165.10 Lund S, Holman GD, Schmitz O and Pedersen O. Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulinJ. Proc Natl Acad Sci U S A, 1995, 92:5817-5821.11 Brozinick JT, Jr. and Birnbaum MJ. Insulin, but

15、not contraction, activates Akt/PKB in isolated rat skeletal muscleJ. J Biol Chem, 1998, 273:14679-14682.12 Dumke CL, Wetter AC, Arias EB, Kahn CR and Cartee GD. Absence of insulin receptor substrate-1 expression does not alter GLUT1 or GLUT4 abundance or contraction-stimulated glucose uptake by mous

16、e skeletal muscleJ. Horm Metab Res, 2001, 33:696-700.13 Sakamoto K, Arnolds DE, Fujii N, Kramer HF, Hirshman MF and Goodyear LJ. Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscleJ. Am J Physiol Endocrinol Metab, 2006, 291:E1031-1037.14 Constable SH, Favier R

17、J, Cartee GD, Young DA and Holloszy JO. Muscle glucose transport: interactions of in vitro contractions, insulin, and exerciseJ. J Appl Physiol, 1988, 64:2329-2332.15 Gao J, Ren J, Gulve EA and Holloszy JO. Additive effect of contractions and insulin on GLUT-4 translocation into the sarcolemmaJ. J A

18、ppl Physiol, 1994, 77:1597-1601.16 Martin IK, Katz A and Wahren J. Splanchnic and muscle metabolism during exercise in NIDDM patientsJ. Am J Physiol, 1995, 269:E583-590.17 Han X, Ploug T and Galbo H. Effect of diet on insulin- and contraction-mediated glucose transport and uptake in rat muscleJ. Am

19、J Physiol, 1995, 269:R544-551.18 King PA, Betts JJ, Horton ED and Horton ES. Exercise, unlike insulin, promotes glucose transporter translocation in obese Zucker rat muscleJ. Am J Physiol, 1993, 265:R447-452.19 Brozinick JT, Jr., Etgen GJ, Jr., Yaspelkis BB, 3rd and Ivy JL. Contraction-activated glu

20、cose uptake is normal in insulin-resistant muscle of the obese Zucker ratJ. J Appl Physiol, 1992, 73:382-387.20 Arias EB, Kim J, Funai K and Cartee GD. Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscleJ. Am J Physiol Endocrinol Metab, 2007, 292:E1191

21、-1200.21 Funai K, Schweitzer GG, Castorena CM, Kanzaki M and Cartee GD. In vivo exercise followed by in vitro contraction additively elevates subsequent insulin-stimulated glucose transport by rat skeletal muscleJ. Am J Physiol Endocrinol Metab, 2010, 298:E999-1010.22 Howlett KF, Mathews A, Garnham

22、A and Sakamoto K. The effect of exercise and insulin on AS160 phosphorylation and 14-3-3 binding capacity in human skeletal muscleJ. Am J Physiol Endocrinol Metab, 2008, 294:E401-407.23 Pehmoller C, Treebak JT, Birk JB, Chen S, Mackintosh C, Hardie DG, Richter EA and Wojtaszewski JF. Genetic disrupt

23、ion of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscleJ. Am J Physiol Endocrinol Metab, 2009, 297:E665-675.24 Jakobsen SN, Hardie DG, Morrice N and Tornqvist HE. 5'-AMP-activated protein kinase phosphorylates IR

24、S-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide ribosideJ. J Biol Chem, 2001, 276:46912-46916.25 Zakikhani M, Blouin MJ, Piura E and Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cellsJ. Breast Canc

25、er Res Treat, 2010, 123:271-279.26 Chopra I, Li HF, Wang H and Webster KA. Phosphorylation of the insulin receptor by AMP-activated protein kinase (AMPK) promotes ligand-independent activation of the insulin signalling pathway in rodent muscleJ. Diabetologia, 2012, 55:783-794.27 Kamon J, Yamauchi T,

26、 Terauchi Y, Kubota N and Kadowaki T. The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolismJ. Nihon Yakurigaku Zasshi, 2003, 122:294-300.28 Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, F

27、oufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB and Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinaseJ. Nat Med, 2002, 8:1288-1295.29 Geiger PC, Hancock C, Wright DC, Han DH and Holloszy JO. IL-6 increases muscle insulin sensitivity only at superphysiological levelsJ. Am J Physiol Endocrinol Metab, 2007, 292:E1842-1846.30 Lee-Young RS, Canny BJ, Myers DE and McConell GK. AMPK activation is fibe