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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health

Author(s): Y.V. Madhavi, Nikhil Gaikwad , Veera Ganesh Yerra , Anil Kumar Kalvala , Srinivas Nanduri and Ashutosh Kumar*

Volume 26 , Issue 27 , 2019

Page: [5207 - 5229] Pages: 23

DOI: 10.2174/0929867325666180406120051

Price: $65


Adenosine 5′-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.

Keywords: Diabetes, diabetic complications, AMPK, autophagy, mitochondria, (AICA riboside), A769662.

Zimmet, P.Z. Diabetes and its drivers: the largest epidemic in human history? Clin. Diabetes Endocrinol., 2017, 3(1), 1.
[] [PMID: 28702255]
Federation, I.D. IDF diabetes atlas 7th Edition; 2930229853; Brussels. ; , 2015.
Fowler, M.J. Microvascular and macrovascular complications of diabetes. Clin. Diabetes, 2008, 26(2), 77-82.
Deshpande, A.D.; Harris-Hayes, M.; Schootman, M. Epidemiology of diabetes and diabetes-related complications. Phys. Ther., 2008, 88(11), 1254-1264.
[] [PMID: 18801858]
Hardie, D.G. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev., 2011, 25(18), 1895-1908.
[] [PMID: 21937710]
Sanz, P. AMP-activated protein kinase: structure and regulation. Curr. Protein Pept. Sci., 2008, 9(5), 478-492.
[] [PMID: 18855699]
Herzig, S.; Shaw, R.J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol., 2018, 19(2), 121-135.
[] [PMID: 28974774]
Hawley, S.A.; Davison, M.; Woods, A.; Davies, S.P.; Beri, R.K.; Carling, D.; Hardie, D.G. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem., 1996, 271(44), 27879-27887.
[] [PMID: 8910387]
Mihaylova, M.M.; Shaw, R.J. The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism. Nat. Cell Biol., 2011, 13(9), 1016.
[] [PMID: 21892142]
Ikeda, Y.; Sato, K.; Pimentel, D.R.; Sam, F.; Shaw, R.J.; Dyck, J.R.; Walsh, K. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J. Biol. Chem., 2009, 284(51), 35839-35849.
[] [PMID: 19828446]
Yerra, V.G.; Kalvala, A.K.; Kumar, A. Isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by SIRT1 activation in experimental diabetic neuropathy. J. Nutr. Biochem., 2017, 47, 41-52.
[] [PMID: 28528294]
Dugan, L.L.; You, Y-H.; Ali, S.S.; Diamond-Stanic, M.; Miyamoto, S.; DeCleves, A-E.; Andreyev, A.; Quach, T.; Ly, S.; Shekhtman, G.; Nguyen, W.; Chepetan, A.; Le, T.P.; Wang, L.; Xu, M.; Paik, K.P.; Fogo, A.; Viollet, B.; Murphy, A.; Brosius, F.; Naviaux, R.K.; Sharma, K. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest., 2013, 123(11), 4888-4899.
[] [PMID: 24135141]
Shan, T.; Zhang, P.; Bi, P.; Kuang, S. Lkb1 deletion promotes ectopic lipid accumulation in muscle progenitor cells and mature muscles. J. Cell. Physiol., 2015, 230(5), 1033-1041.
[] [PMID: 25251157]
Hardie, D.G.; Ross, F.A.; Hawley, S.A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol., 2012, 13(4), 251-262.
[] [PMID: 22436748]
Davies, S.P.; Carling, D.; Munday, M.R.; Hardie, D.G. Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. Eur. J. Biochem., 1992, 203(3), 615-623.
[] [PMID: 1346520]
Muoio, D.M.; Seefeld, K.; Witters, L.A.; Coleman, R.A. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem. J., 1999, 338(Pt 3), 783-791.
[] [PMID: 10051453]
Clarke, P.R.; Hardie, D.G. Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J., 1990, 9(8), 2439-2446.
[] [PMID: 2369897]
Jørgensen, S.B.; Nielsen, J.N.; Birk, J.B.; Olsen, G.S.; Viollet, B.; Andreelli, F.; Schjerling, P.; Vaulont, S.; Hardie, D.G.; Hansen, B.F.; Richter, E.A.; Wojtaszewski, J.F. The α2-5'AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes, 2004, 53(12), 3074-3081.
[] [PMID: 15561936]
Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell, 2008, 30(2), 214-226.
[] [PMID: 18439900]
Hoppe, S.; Bierhoff, H.; Cado, I.; Weber, A.; Tiebe, M.; Grummt, I.; Voit, R. AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. Proc. Natl. Acad. Sci. USA, 2009, 106(42), 17781-17786.
[] [PMID: 19815529]
Li, Y.; Xu, S.; Mihaylova, M.M.; Zheng, B.; Hou, X.; Jiang, B.; Park, O.; Luo, Z.; Lefai, E.; Shyy, J.Y-J.; Gao, B.; Wierzbicki, M.; Verbeuren, T.J.; Shaw, R.J.; Cohen, R.A.; Zang, M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab., 2011, 13(4), 376-388.
[] [PMID: 21459323]
Koo, S-H.; Flechner, L.; Qi, L.; Zhang, X.; Screaton, R.A.; Jeffries, S.; Hedrick, S.; Xu, W.; Boussouar, F.; Brindle, P.; Takemori, H.; Montminy, M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature, 2005, 437(7062), 1109-1111.
[] [PMID: 16148943]
Barnes, K.; Ingram, J.C.; Porras, O.H.; Barros, L.F.; Hudson, E.R.; Fryer, L.G.; Foufelle, F.; Carling, D.; Hardie, D.G.; Baldwin, S.A. Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J. Cell Sci., 2002, 115(Pt 11), 2433-2442.
[PMID: 12006627]
Habets, D.D.; Coumans, W.A.; El Hasnaoui, M.; Zarrinpashneh, E.; Bertrand, L.; Viollet, B.; Kiens, B.; Jensen, T.E.; Richter, E.A.; Bonen, A. Crucial role for LKB1 to AMPKα2 axis in the regulation of CD36-mediated long-chain fatty acid uptake into cardiomyocytes. Biochimica et Biophysica Acta (BBA)-. Molecular and Cell Biology of Lipids, 2009, 1791(3), 212-219.
[] [PMID: 19159696]
Hardie, D.G. AMP-activated protein kinase as a drug target. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 185-210.
[] [PMID: 16879084]
Merrill, G.F.; Kurth, E.J.; Hardie, D.G.; Winder, W.W. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J. Physiol., 1997, 273(6), E1107-E1112.
[PMID: 9435525]
Shibata, R.; Ouchi, N.; Ito, M.; Kihara, S.; Shiojima, I.; Pimentel, D.R.; Kumada, M.; Sato, K.; Schiekofer, S.; Ohashi, K.; Funahashi, T.; Colucci, W.S.; Walsh, K. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat. Med., 2004, 10(12), 1384-1389.
[] [PMID: 15558058]
Shibata, R.; Sato, K.; Pimentel, D.R.; Takemura, Y.; Kihara, S.; Ohashi, K.; Funahashi, T.; Ouchi, N.; Walsh, K. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat. Med., 2005, 11(10), 1096-1103.
[] [PMID: 16155579]
Xie, Z.; He, C.; Zou, M-H. AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy. Autophagy, 2011, 7(10), 1254-1255.
[] [PMID: 21685727]
Jornayvaz, F.R.; Shulman, G.I. Regulation of mitochondrial biogenesis. Essays Biochem., 2010, 47, 69-84.
[] [PMID: 20533901]
Jäger, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl. Acad. Sci. USA, 2007, 104(29), 12017-12022.
[] [PMID: 17609368]
Cantó, C.; Jiang, L.Q.; Deshmukh, A.S.; Mataki, C.; Coste, A.; Lagouge, M.; Zierath, J.R.; Auwerx, J. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab., 2010, 11(3), 213-219.
[] [PMID: 20197054]
Egan, D.F.; Shackelford, D.B.; Mihaylova, M.M.; Gelino, S.; Kohnz, R.A.; Mair, W.; Vasquez, D.S.; Joshi, A.; Gwinn, D.M.; Taylor, R.; Asara, J.M.; Fitzpatrick, J.; Dillin, A.; Viollet, B.; Kundu, M.; Hansen, M.; Shaw, R.J. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science, 2011, 331(6016), 456-461.
[] [PMID: 21205641]
Palikaras, K.; Tavernarakis, N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp. Gerontol., 2014, 56, 182-188.
[] [PMID: 24486129]
Yang, Y.; Atasoy, D.; Su, H.H.; Sternson, S.M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell, 2011, 146(6), 992-1003.
[] [PMID: 21925320]
McCrimmon, R.J.; Shaw, M.; Fan, X.; Cheng, H.; Ding, Y.; Vella, M.C.; Zhou, L.; McNay, E.C.; Sherwin, R.S. Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes, 2008, 57(2), 444-450.
[] [PMID: 17977955]
Lamia, K.A.; Sachdeva, U.M.; DiTacchio, L.; Williams, E.C.; Alvarez, J.G.; Egan, D.F.; Vasquez, D.S.; Juguilon, H.; Panda, S.; Shaw, R.J.; Thompson, C.B.; Evans, R.M. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science, 2009, 326(5951), 437-440.
[] [PMID: 19833968]
Handen, B.L.; Anagnostou, E.; Aman, M.G.; Sanders, K.B.; Chan, J.; Hollway, J.A.; Brian, J.; Arnold, L.E.; Capano, L.; Williams, C.; Hellings, J.A.; Butter, E.; Mankad, D.; Tumuluru, R.; Kettel, J.; Newsom, C.R.; Peleg, N.; Odrobina, D.; McAuliffe-Bellin, S.; Marler, S.; Wong, T.; Wagner, A.; Hadjiyannakis, S.; Macklin, E.A.; Veenstra-VanderWeele, J. A randomized, placebo-controlled trial of metformin for the treatment of overweight induced by antipsychotic medication in young people with autism spectrum disorder: open-label extension. J. Am. Acad. Child Adolesc. Psychiatry, 2017, 56(10), 849-856, e6.
[] [PMID: 28942807]
Kumsun Cho, J.Y.C. Sung Kweon Cho, Hyun-Woo Shin, In-Jin Jang, Jong-Wan Park, Kyung-Sang Yu, Joo-Youn Cho., Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRa/POMC pathway. Sci. Rep., 2015, 5, 8145.
[PMID: 25634597]
Ouyang, J.; Parakhia, R.A.; Ochs, R.S. Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem., 2011, 286(1), 1-11.
[] [PMID: 21059655]
Kumari, V.A.; Bharathi, K.; Ponnudurai, K.; Prabhu, K. Synthesis and biological evaluation of N-cinnamoyl and mandelate metformin analogues. Asian J. Chem., 2016, 28(9), 1895-1898.
Liu, J.; Wang, L-N. Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Database Syst. Rev., 2017, 12CD010693
Spiegelman, B.M. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes, 1998, 47(4), 507-514.
[] [PMID: 9568680]
Bays, H.; Mandarino, L.; DeFronzo, R.A. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J. Clin. Endocrinol. Metab., 2004, 89(2), 463-478.
[] [PMID: 14764748]
Raza, S.; Srivastava, S.P.; Srivastava, D.S.; Srivastava, A.K.; Haq, W.; Katti, S.B. Thiazolidin-4-one and thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic agents. Eur. J. Med. Chem., 2013, 63, 611-620.
[] [PMID: 23567949]
Suchankova, G.; Nelson, L.E.; Gerhart-Hines, Z.; Kelly, M.; Gauthier, M.S.; Saha, A.K.; Ido, Y.; Puigserver, P.; Ruderman, N.B. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem. Biophys. Res. Commun., 2009, 378(4), 836-841.
[] [PMID: 19071085]
Soetikno, V.; Sari, F.R.; Sukumaran, V.; Lakshmanan, A.P.; Harima, M.; Suzuki, K.; Kawachi, H.; Watanabe, K. Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats. J. Nutr. Biochem., 2013, 24(5), 796-802.
[] [PMID: 22898567]
Kim, T.; Davis, J.; Zhang, A.J.; He, X.; Mathews, S.T. Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. Biochem. Biophys. Res. Commun., 2009, 388(2), 377-382.
[] [PMID: 19665995]
Zhou, G-Z.; Sun, G-C.; Zhang, S-N. Curcumin derivative HBC induces autophagy through activating AMPK signal in A549 cancer cells. Mol. Cell. Toxicol., 2015, 11(1), 29-34.
Goto, T.; Teraminami, A.; Lee, J-Y.; Ohyama, K.; Funakoshi, K.; Kim, Y-I.; Hirai, S.; Uemura, T.; Yu, R.; Takahashi, N.; Kawada, T. Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice. J. Nutr. Biochem., 2012, 23(7), 768-776.
[] [PMID: 21889885]
Qin, N.; Li, C-B.; Jin, M-N.; Shi, L-H.; Duan, H-Q.; Niu, W-Y. Synthesis and biological activity of novel tiliroside derivants. Eur. J. Med. Chem., 2011, 46(10), 5189-5195.
[] [PMID: 21856048]
Pan, G.; Zhao, L.; Xiao, N.; Yang, K.; Ma, Y.; Zhao, X.; Fan, Z.; Zhang, Y.; Yao, Q.; Lu, K.; Yu, P. Total synthesis of 8-(6″-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents. Eur. J. Med. Chem., 2016, 122, 674-683.
[] [PMID: 27448923]
Gaur, R.; Yadav, K.S.; Verma, R.K.; Yadav, N.P.; Bhakuni, R.S. In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin. Phytomedicine, 2014, 21(4), 415-422.
[] [PMID: 24262065]
Winder, W.W.; Hardie, D.G. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol., 1999, 277(1), E1-E10.
[PMID: 10409121]
Gruzman, A.; Shamni, O.; Ben Yakir, M.; Sandovski, D.; Elgart, A.; Alpert, E.; Cohen, G.; Hoffman, A.; Katzhendler, Y.; Cerasi, E.; Sasson, S. Novel D-xylose derivatives stimulate muscle glucose uptake by activating AMP-activated protein kinase α. J. Med. Chem., 2008, 51(24), 8096-8108.
[] [PMID: 19049348]
Li, W.; Hua, B.; Saud, S.M.; Lin, H.; Hou, W.; Matter, M.S.; Jia, L.; Colburn, N.H.; Young, M.R. Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol. Carcinog., 2015, 54(10), 1096-1109.
[] [PMID: 24838344]
Yin, J.; Hu, R.; Chen, M.; Tang, J.; Li, F.; Yang, Y.; Chen, J. Effects of berberine on glucose metabolism in vitro. Metabolism, 2002, 51(11), 1439-1443.
[] [PMID: 12404195]
Ren, G.Y-X.W. Ying-Hong Li, Dan-Qing Song, Wei-Jia Kong, Jian-Dong Jiang, Structure-activity relationship of berberine derivatives for their glucose-lowering activities. Int. J. Clin. Exp. Med., 2017, 10(3), 5054-5060.
Ahn, J.; Lee, H.; Kim, S.; Park, J.; Ha, T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem. Biophys. Res. Commun., 2008, 373(4), 545-549.
[] [PMID: 18586010]
Shen, Q.W.; Zhu, M.J.; Tong, J.; Ren, J.; Du, M. Ca2+/calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by α-lipoic acid in C2C12 myotubes. Am. J. Physiol. Cell Physiol., 2007, 293(4), C1395-C1403.
[] [PMID: 17687000]
Lakshminarayana, N.; Rajendra Prasad, Y.; Gharat, L.; Thomas, A.; Ravikumar, P.; Narayanan, S.; Srinivasan, C.V.; Gopalan, B. Synthesis and evaluation of some novel isochroman carboxylic acid derivatives as potential anti-diabetic agents. Eur. J. Med. Chem., 2009, 44(8), 3147-3157.
[] [PMID: 19349096]
Rose-Kahn, G.; Bar-Tana, J. Inhibition of lipid synthesis by beta beta’-tetramethyl-substituted, C14-C22, alpha, omega-dicarboxylic acids in cultured rat hepatocytes. J. Biol. Chem., 1985, 260(14), 8411-8415.
[PMID: 4008497]
Lu, J.; Shi, J.; Li, M.; Gui, B.; Fu, R.; Yao, G.; Duan, Z.; Lv, Z.; Yang, Y.; Chen, Z.; Jia, L.; Tian, L. Activation of AMPK by metformin inhibits TGF-β-induced collagen production in mouse renal fibroblasts. Life Sci., 2015, 127, 59-65.
[] [PMID: 25744403]
Vingtdeux, V.; Chandakkar, P.; Zhao, H.; Davies, P.; Marambaud, P. Small-molecule activators of AMP-activated protein kinase (AMPK), RSVA314 and RSVA405, inhibit adipogenesis. Mol. Med., 2011, 17(9-10), 1022-1030.
[] [PMID: 21647536]
Erbay, E.; Babaev, V.R.; Mayers, J.R.; Makowski, L.; Charles, K.N.; Snitow, M.E.; Fazio, S.; Wiest, M.M.; Watkins, S.M.; Linton, M.F.; Hotamisligil, G.S. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat. Med., 2009, 15(12), 1383-1391.
[] [PMID: 19966778]
Corton, J.M.; Gillespie, J.G.; Hawley, S.A.; Hardie, D.G. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem., 1995, 229(2), 558-565.
[] [PMID: 7744080]
Zhang, L-N.; Xu, L.; Zhou, H-Y.; Wu, L-Y.; Li, Y-Y.; Pang, T.; Xia, C-M.; Qiu, B-Y.; Gu, M.; Dong, T-C.; Li, J-Y.; Shen, J-K.; Li, J. Novel small-molecule AMP-activated protein kinase allosteric activator with beneficial effects in db/db mice. PLoS One, 2013, 8(8)e72092
[] [PMID: 23977216]
Hawley, S.A.; Fullerton, M.D.; Ross, F.A.; Schertzer, J.D.; Chevtzoff, C.; Walker, K.J.; Peggie, M.W.; Zibrova, D.; Green, K.A.; Mustard, K.J.; Kemp, B.E.; Sakamoto, K.; Steinberg, G.R.; Hardie, D.G. The ancient drug salicylate directly activates AMP-activated protein kinase. Science, 2012, 336(6083), 918-922.
[] [PMID: 22517326]
Kim, J.; Yang, G.; Kim, Y.; Kim, J.; Ha, J. AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med., 2016, 48(4)e224
[] [PMID: 27034026]
Zhou, G.; Sebhat, I.K.; Zhang, B.B. AMPK activators--potential therapeutics for metabolic and other diseases. Acta Physiol. (Oxf.), 2009, 196(1), 175-190.
[] [PMID: 19245659]
Sanders, M.J.; Ali, Z.S.; Hegarty, B.D.; Heath, R.; Snowden, M.A.; Carling, D. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J. Biol. Chem., 2007, 282(45), 32539-32548.
[] [PMID: 17728241]
Hallakou-Bozec, S.; Charon, C.; Pöschke, O. HOCK, B., Use of thienopyridone derivatives as AMPK activators and pharmaceutical compositions containing them; Google Patents, 2007.
Cameron, K.O.; Kung, D.W.; Kalgutkar, A.S.; Kurumbail, R.G.; Miller, R.; Salatto, C.T.; Ward, J.; Withka, J.M.; Bhattacharya, S.K.; Boehm, M.; Borzilleri, K.A.; Brown, J.A.; Calabrese, M.; Caspers, N.L.; Cokorinos, E.; Conn, E.L.; Dowling, M.S.; Edmonds, D.J.; Eng, H.; Fernando, D.P.; Frisbie, R.; Hepworth, D.; Landro, J.; Mao, Y.; Rajamohan, F.; Reyes, A.R.; Rose, C.R.; Ryder, T.; Shavnya, A.; Smith, A.C.; Tu, M.; Wolford, A.C.; Xiao, J. Discovery and preclinical characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid (PF-06409577), a direct activator of adenosine monophosphate-activated protein kinase (AMPK), for the potential treatment of diabetic nephropathy. J. Med. Chem., 2016, 59(17), 8068-8081.
[] [PMID: 27490827]
Gómez-Galeno, J.E.; Dang, Q.; Nguyen, T.H.; Boyer, S.H.; Grote, M.P.; Sun, Z.; Chen, M.; Craigo, W.A.; van Poelje, P.D.; MacKenna, D.A.; Cable, E.E.; Rolzin, P.A.; Finn, P.D.; Chi, B.; Linemeyer, D.L.; Hecker, S.J.; Erion, M.D. A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med. Chem. Lett., 2010, 1(9), 478-482.
[] [PMID: 24900234]
Pang, T.; Zhang, Z-S.; Gu, M.; Qiu, B-Y.; Yu, L-F.; Cao, P-R.; Shao, W.; Su, M-B.; Li, J-Y.; Nan, F-J.; Li, J. Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J. Biol. Chem., 2008, 283(23), 16051-16060.
[] [PMID: 18321858]
Oh, S.; Kim, S.J.; Hwang, J.H.; Lee, H.Y.; Ryu, M.J.; Park, J.; Kim, S.J.; Jo, Y.S.; Kim, Y.K.; Lee, C-H.; Kweon, K.R.; Shong, M.; Park, S.B. Antidiabetic and antiobesity effects of Ampkinone (6f), a novel small molecule activator of AMP-activated protein kinase. J. Med. Chem., 2010, 53(20), 7405-7413.
[] [PMID: 20873794]
McCullough, L.D.; Zeng, Z.; Li, H.; Landree, L.E.; McFadden, J.; Ronnett, G.V. Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J. Biol. Chem., 2005, 280(21), 20493-20502.
[] [PMID: 15772080]
Yu, P.B.; Hong, C.C.; Sachidanandan, C.; Babitt, J.L.; Deng, D.Y.; Hoyng, S.A.; Lin, H.Y.; Bloch, K.D.; Peterson, R.T. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol., 2008, 4(1), 33-41.
[] [PMID: 18026094]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[] [PMID: 11602624]
Misra, P.; Chakrabarti, R. The role of AMP kinase in diabetes. Indian J. Med. Res., 2007, 125(3), 389-398.
[PMID: 17496363]
Chen, S.; Murphy, J.; Toth, R.; Campbell, D.G.; Morrice, N.A.; Mackintosh, C. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem. J., 2008, 409(2), 449-459.
[] [PMID: 17995453]
Coughlan, K.A.; Valentine, R.J.; Ruderman, N.B.; Saha, A.K. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab. Syndr. Obes., 2014, 7, 241-253.
[PMID: 25018645]
Merrill, G.; Kurth, E.; Hardie, D.; Winder, W. AICAR decreases malonyl-CoA and increases fatty acid oxidation in skeletal muscle of the rat. Am. J. Physiol., 1997, 273, E1107-E1112.
[PMID: 9435525]
Reddy, M.A.; Zhang, E.; Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia, 2015, 58(3), 443-455.
[] [PMID: 25481708]
Yao, F.; Zhang, M.; Chen, L. 5′-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications. Acta Pharm. Sin. B, 2016, 6(1), 20-25.
[] [PMID: 26904395]
Dugan, L.L.; You, Y-H.; Ali, S.S.; Diamond-Stanic, M.; Miyamoto, S.; DeCleves, A-E.; Andreyev, A.; Quach, T.; Ly, S.; Shekhtman, G.; Nguyen, W.; Chepetan, A.; Le, T.P.; Wang, L.; Xu, M.; Paik, K.P.; Fogo, A.; Viollet, B.; Murphy, A.; Brosius, F.; Naviaux, R.K.; Sharma, K. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest., 2013, 123(11), 4888-4899.
[] [PMID: 24135141]
Yerra, V.G.; Areti, A.; Kumar, A. Adenosine monophosphate-activated protein kinase abates hyperglycaemia-induced neuronal injury in experimental models of diabetic neuropathy: effects on mitochondrial biogenesis, autophagy and neuroinflammation. Mol. Neurobiol., 2017, 54(3), 2301-2312.
[] [PMID: 26957299]
Kume, S.; Thomas, M.C.; Koya, D. Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes, 2012, 61(1), 23-29.
[] [PMID: 22187371]
Higgins, G.C.; Coughlan, M.T. Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br. J. Pharmacol., 2014, 171(8), 1917-1942.
[] [PMID: 24720258]
Pangare, M.; Makino, A. Mitochondrial function in vascular endothelial cell in diabetes. J. Smooth Muscle Res., 2012, 48(1), 1-26.
[] [PMID: 22504486]
Bai, T.; Wang, F.; Zheng, Y.; Liang, Q.; Wang, Y.; Kong, J.; Cai, L. Myocardial redox status, mitophagy and cardioprotection: a potential way to amend diabetic heart? Clin. Sci. (Lond.), 2016, 130(17), 1511-1521.
[] [PMID: 27433024]
Kubota, S.; Ozawa, Y.; Kurihara, T.; Sasaki, M.; Yuki, K.; Miyake, S.; Noda, K.; Ishida, S.; Tsubota, K. Roles of AMP-activated protein kinase in diabetes-induced retinal inflammation. Invest. Ophthalmol. Vis. Sci., 2011, 52(12), 9142-9148.
[] [PMID: 22058332]
Zhao, L.; Sun, L-N.; Nie, H-B.; Wang, X-L.; Guan, G-J. Berberine improves kidney function in diabetic mice via AMPK activation. PLoS One, 2014, 9(11)e113398
[] [PMID: 25409232]
Hallows, K.R.; Mount, P.F.; Pastor-Soler, N.M.; Power, D.A. Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. Am. J. Physiol. Renal Physiol., 2010, 298(5), F1067-F1077.
[] [PMID: 20181668]
Luo, X.; Deng, L.; Lamsal, L.P.; Xu, W.; Xiang, C.; Cheng, L. AMP-activated protein kinase alleviates extracellular matrix accumulation in high glucose-induced renal fibroblasts through mTOR signaling pathway. Cell. Physiol. Biochem., 2015, 35(1), 191-200.
[] [PMID: 25591762]
Chen, K-H.; Hsu, H-H.; Lee, C-C.; Yen, T-H.; Ko, Y-C.; Yang, C-W.; Hung, C-C. The AMPK agonist AICAR inhibits TGF-β1 induced activation of kidney myofibroblasts. PLoS One, 2014, 9(9)e106554
[] [PMID: 25188319]
Yu, J-W.; Deng, Y-P.; Han, X.; Ren, G-F.; Cai, J.; Jiang, G-J. Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK/eNOS pathway in diabetic mice. Cardiovasc. Diabetol., 2016, 15(1), 88.
[] [PMID: 27316923]
Ewart, M-A.; Kennedy, S. AMPK and vasculoprotection. Pharmacol. Ther., 2011, 131(2), 242-253.
[] [PMID: 21111758]
Hardie, D.G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes, 2013, 62(7), 2164-2172.
[] [PMID: 23801715]
Wall, C.E.; Yu, R.T.; Atkins, A.R.; Downes, M.; Evans, R.M. Nuclear receptors and AMPK: can exercise mimetics cure diabetes? J. Mol. Endocrinol., 2016, 57(1), R49-R58.
[] [PMID: 27106806]
Jin, Y.; Liu, S.; Ma, Q.; Xiao, D.; Chen, L. Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes. Eur. J. Pharmacol., 2017, 794, 106-114.
[] [PMID: 27887947]
Chen, K.; Li, G.; Geng, F.; Zhang, Z.; Li, J.; Yang, M.; Dong, L.; Gao, F. Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats. Apoptosis, 2014, 19(6), 946-957.
[] [PMID: 24664781]
Wang, Y.; Huang, Y.; Lam, K.S.; Li, Y.; Wong, W.T.; Ye, H.; Lau, C-W.; Vanhoutte, P.M.; Xu, A. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc. Res., 2009, 82(3), 484-492.
[] [PMID: 19251722]
Kitada, M.; Kume, S.; Imaizumi, N.; Koya, D. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes, 2011, 60(2), 634-643.
[] [PMID: 21270273]
Roy Chowdhury, S.K.; Smith, D.R.; Saleh, A.; Schapansky, J.; Marquez, A.; Gomes, S.; Akude, E.; Morrow, D.; Calcutt, N.A.; Fernyhough, P. Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain, 2012, 135(Pt 6), 1751-1766.
[] [PMID: 22561641]
Kim, M.Y.; Lim, J.H.; Youn, H.H.; Hong, Y.A.; Yang, K.S.; Park, H.S.; Chung, S.; Ko, S.H.; Shin, S.J.; Choi, B.S.; Kim, H.W.; Kim, Y.S.; Lee, J.H.; Chang, Y.S.; Park, C.W. Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice. Diabetologia, 2013, 56(1), 204-217.
[] [PMID: 23090186]
Guo, S.; Yao, Q.; Ke, Z.; Chen, H.; Wu, J.; Liu, C. Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK. Mol. Cell. Endocrinol., 2015, 412, 85-94.
[] [PMID: 26054749]
Penumathsa, S.V.; Thirunavukkarasu, M.; Zhan, L.; Maulik, G.; Menon, V.P.; Bagchi, D.; Maulik, N. Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/Akt/eNOS signalling pathway in diabetic myocardium. J. Cell. Mol. Med., 2008, 12(6A), 2350-2361.
[] [PMID: 18266981]
Liu, Z.; Jiang, C.; Zhang, J.; Liu, B.; Du, Q. Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities. J. Diabetes, 2016, 8(3), 324-335.
[] [PMID: 25850408]
Lee, M-J.; Feliers, D.; Mariappan, M.M.; Sataranatarajan, K.; Mahimainathan, L.; Musi, N.; Foretz, M.; Viollet, B.; Weinberg, J.M.; Choudhury, G.G.; Kasinath, B.S. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am. J. Physiol. Renal Physiol., 2007, 292(2), F617-F627.
[] [PMID: 17018841]
Ma, J.; Yu, H.; Liu, J.; Chen, Y.; Wang, Q.; Xiang, L. Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur. J. Pharmacol., 2015, 764, 599-606.
[] [PMID: 26054810]
Hasanvand, A.; Amini-Khoei, H.; Hadian, M-R.; Abdollahi, A.; Tavangar, S.M.; Dehpour, A.R.; Semiei, E.; Mehr, S.E. Anti-inflammatory effect of AMPK signaling pathway in rat model of diabetic neuropathy. Inflammopharmacology, 2016, 24(5), 207-219.
[] [PMID: 27506528]
Calvert, J.W.; Gundewar, S.; Jha, S.; Greer, J.J.; Bestermann, W.H.; Tian, R.; Lefer, D.J. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes, 2008, 57(3), 696-705.
[] [PMID: 18083782]
Ceolotto, G.; Gallo, A.; Papparella, I.; Franco, L.; Murphy, E.; Iori, E.; Pagnin, E.; Fadini, G.P.; Albiero, M.; Semplicini, A.; Avogaro, A. Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler. Thromb. Vasc. Biol., 2007, 27(12), 2627-2633.
[] [PMID: 17916771]
Soetikno, V.; Sari, F.R.; Sukumaran, V.; Lakshmanan, A.P.; Harima, M.; Suzuki, K.; Kawachi, H.; Watanabe, K. Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats. J. Nutr. Biochem., 2013, 24(5), 796-802.
[] [PMID: 22898567]

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