Abstract
AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular “fuel deficiency.” AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP generation—most notably metformin and berberine—can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators—as reflected by their efficacy in diabetes management—regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of health-protective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.
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Abbasi F, Kamath V, Rizvi AA, Carantoni M, Chen YD, Reaven GM (1997) Results of a placebo-controlled study of the metabolic effects of the addition of metformin to sulfonylurea-treated patients. Evidence for a central role of adipose tissue. Diabetes Care 20(12):1863–1869
Abbasi F, Carantoni M, Chen YD, Reaven GM (1998) Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care 21(8):1301–1305
Abidi P, Zhou Y, Jiang JD, Liu J (2005) Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine. Arterioscler Thromb Vasc Biol 25(10):2170–2176
Ahmad R, Sylvester J, Ahmad M, Zafarullah M (2011) Involvement of H-Ras and reactive oxygen species in proinflammatory cytokine-induced matrix metalloproteinase-13 expression in human articular chondrocytes. Arch Biochem Biophys 507(2):350–355
Alba G, El Bekay R, varez-Maqueda M et al (2004) Stimulators of AMP-activated protein kinase inhibit the respiratory burst in human neutrophils. FEBS Lett 573(1–3):219–225
Anisimov VN (2010) Metformin for aging and cancer prevention. Aging (Albany NY) 2(11):760–774
Anisimov VN, Berstein LM, Popovich IG et al (2011) If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY) 3(2):148–157
Arad M, Moskowitz IP, Patel VV et al (2003) Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff–Parkinson–White syndrome in glycogen storage cardiomyopathy. Circulation 107(22):2850–2856
Armour KE, Armour KJ, Gallagher ME et al (2001) Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase. Endocrinology 142(2):760–766
Athar M, Elmets CA, Kopelovich L (2011) Pharmacological activation of p53 in cancer cells. Curr Pharm Des 17(6):631–639
Attane C, Foussal C, Le GS et al (2012) Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 61(2):310–320
Austin SA, Santhanam AV, Katusic ZS (2010) Endothelial nitric oxide modulates expression and processing of amyloid precursor protein. Circ Res 107(12):1498–1502
Bai A, Yong M, Ma AG et al (2010a) Novel anti-inflammatory action of 5-aminoimidazole-4-carboxamide ribonucleoside with protective effect in dextran sulfate sodium-induced acute and chronic colitis. J Pharmacol Exp Ther 333(3):717–725
Bai A, Ma AG, Yong M et al (2010b) AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem Pharmacol 80(11):1708–1717
Banerjee R, Beal MF, Thomas B (2010) Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 33(12):541–549
Bartke A (2005) Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146(9):3718–3723
Battu SK, Repka MA, Maddineni S, Chittiboyina AG, Avery MA, Majumdar S (2010) Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery. AAPS PharmSciTech 11(3):1466–1475
Baur JA, Pearson KJ, Price NL et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342
Beauloye C, Bertrand L, Horman S, Hue L (2011) AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. Cardiovasc Res 90(2):224–233
Benes J, Kazdova L, Drahota Z et al (2011) Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. Clin Sci (Lond) 121(1):29–41
Ben-Shlomo S, Zvibel I, Shnell M et al (2011) Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol 54(6):1214–1223
Bergamini E, Cavallini G, Cecchi L et al (1998) A proposed mechanism of the antiaging action of diet restriction. Aging (Milano) 10(2):174–175
Bess E, Fisslthaler B, Fromel T, Fleming I (2011) Nitric oxide-induced activation of the AMP-activated protein kinase alpha2 subunit attenuates IkappaB kinase activity and inflammatory responses in endothelial cells. PLoS ONE 6(6):e20848
Blagosklonny MV (2010) Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 9(4):683–688
Bo S, Ciccone G, Rosato R et al (2012) Cancer mortality reduction and metformin. A retrospective cohort study in type 2 diabetic patients. Diabetes Obes Metab 14(1):23–29
Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR, Meier CR (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33(6):1304–1308
Boocock DJ, Faust GE, Patel KR et al (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16(6):1246–1252
Bowker SL, Yasui Y, Veugelers P, Johnson JA (2010) Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia 53(8):1631–1637
Brown GC (2007) Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase. Biochem Soc Trans 35(Pt 5):1119–1121
Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR, Simpson ER (2009) Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. Cancer Res 69(13):5392–5399
Brown KA, Hunger NI, Docanto M, Simpson ER (2010) Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 123(2):591–596
Bulcao C, Ribeiro-Filho FF, Sanudo A, Roberta Ferreira SG (2007) Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. Am J Cardiovasc Drugs 7(3):219–224
Canto C, Auwerx J (2011) Calorie Restriction: is AMPK a key sensor and effector? Physiology (Bethesda) 26(4):214–224
Canto C, Gerhart-Hines Z, Feige JN et al (2009) AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1 activity. Nature 458(7241):1056–1060
Canto C, Jiang LQ, Deshmukh AS et al (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11(3):213–219
Carling D, Mayer FV, Sanders MJ, Gamblin SJ (2011) AMP-activated protein kinase: nature's energy sensor. Nat Chem Biol 7(8):512–518
Cartee GD, Wojtaszewski JF (2007) Role of Akt substrate of 160 kDa in insulin-stimulated and contraction-stimulated glucose transport. Appl Physiol Nutr Metab 32(3):557–566
Ceolotto G, Gallo A, Papparella I et al (2007) Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler Thromb Vasc Biol 27(12):2627–2633
Chari NS, Pinaire NL, Thorpe L, Medeiros LJ, Routbort MJ, McDonnell TJ (2009) The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death. Apoptosis 14(4):336–347
Chen ZP, Mitchelhill KI, Michell BJ et al (1999) AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 443(3):285–289
Chen Z, Peng IC, Sun W et al (2009a) AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res 104(4):496–505
Chen Y, Zhou K, Wang R et al (2009b) Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A 106(10):3907–3912
Ching YP, Davies SP, Hardie DG (1996) Analysis of the specificity of the AMP-activated protein kinase by site-directed mutagenesis of bacterially expressed 3-hydroxy 3-methylglutaryl-CoA reductase, using a single primer variant of the unique-site-elimination method. Eur J Biochem 237(3):800–808
Chong ZZ, Shang YC, Zhang L, Wang S, Maiese K (2010) Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxidative Med Cell Longev 3(6):374–391
Cicero AF, Rovati LC, Setnikar I (2007) Eulipidemic effects of berberine administered alone or in combination with other natural cholesterol-lowering agents. A single-blind clinical investigation. Arzneimittelforschung 57(1):26–30
Colombo SL, Moncada S (2009) AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. Biochem J 421(2):163–169
Cooke JP (2004) The pivotal role of nitric oxide for vascular health. Can J Cardiol 20(Suppl B):7B–15B
Cool B, Zinker B, Chiou W et al (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3(6):403–416
Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L (2006) Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 536(1–2):38–46
Cuervo AM (2008) Calorie restriction and aging: the ultimate “cleansing diet”. J Gerontol A Biol Sci Med Sci 63(6):547–549
Culjkovic B, Topisirovic I, Borden KL (2007) Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E. Cell Cycle 6(1):65–69
Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52(9):1766–1777
Dagher Z, Ruderman N, Tornheim K, Ido Y (2001) Acute regulation of fatty acid oxidation and amp-activated protein kinase in human umbilical vein endothelial cells. Circ Res 88(12):1276–1282
Dao TM, Waget A, Klopp P et al (2011) Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control. PLoS ONE 6(6):e20700
De Leo V, La Marca A, Orvieto R, Morgante G (2000) Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome. J Clin Endocrinol Metab 85(4):1598–1600
De BA, Graff JR (2004) eIF-4E expression and its role in malignancies and metastases. Oncogene 23(18):3189–3199
Decensi A, Puntoni M, Goodwin P et al (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461
Dellavalle A, Maroli G, Covarello D et al (2011) Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat Commun 2:499
Deng G, Long Y, Yu YR, Li MR (2010) Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK-eNOS Pathway. Int J Obes (Lond) 34(1):165–171
Desilets AR, Dhakal-Karki S, Dunican KC (2008) Role of metformin for weight management in patients without type 2 diabetes. Ann Pharmacother 42(6):817–826
Dhahbi JM, Mote PL, Fahy GM, Spindler SR (2005) Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 23(3):343–350
Di MS, Mazroui R, Dallaire P et al (2005) NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release. Mol Cell Biol 25(15):6533–6545
Diogo CV, Machado NG, Barbosa IA, Serafim TL, Burgeiro A, Oliveira PJ (2011) Berberine as a promising safe anti-cancer agent—is there a role for mitochondria? Curr Drug Targets 12(6):850–859
Dolinsky VW, Morton JS, Oka T et al (2010) Calorie restriction prevents hypertension and cardiac hypertrophy in the spontaneously hypertensive rat. Hypertension 56(3):412–421
Dowling RJ, Goodwin PJ, Stambolic V (2011) Understanding the benefit of metformin use in cancer treatment. BMC Med 9:33
Drew BG, Fidge NH, Gallon-Beaumier G, Kemp BE, Kingwell BA (2004) High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation. Proc Natl Acad Sci U S A 101(18):6999–7004
Egan D, Kim J, Shaw RJ, Guan KL (2011) The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7(6):643–644
El-Assaad W, Buteau J, Peyot ML et al (2003) Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 144(9):4154–4163
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330(7503):1304–1305
Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail-Beigi F, Amini M (2013) Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes. Acta Diabetol 50(4):537–543
Faubert B, Boily G, Izreig S et al (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124
Fidan E, Onder EH, Yilmaz M et al (2011) The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus. Acta Diabetol 48(4):297–302
Foretz M, Ancellin N, Andreelli F et al (2005) Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes 54(5):1331–1339
Freeland KR, Wolever TM (2010) Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha. Br J Nutr 103(3):460–466
Fu YN, Xiao H, Ma XW, Jiang SY, Xu M, Zhang YY (2011) Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation. Acta Pharmacol Sin 32(7):879–887
Fu X, Zhao JX, Liang J, Zhu MJ, Viollet B, Du M (2013) AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5. Am J Physiol Cell Physiol 305(8):C887–C895
Fulco M, Cen Y, Zhao P et al (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 14(5):661–673
Gao Y, Li Y, Xue J, Jia Y, Hu J (2010) Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol 635(1–3):231–236
Gao N, Zhao TY, Li XJ (2011) The protective effect of berberine on beta-cell lipoapoptosis. J Endocrinol Invest 34(2):124–130
Garton AJ, Yeaman SJ (1990) Identification and role of the basal phosphorylation site on hormone-sensitive lipase. Eur J Biochem 191(1):245–250
Geisler J, Haynes B, Ekse D, Dowsett M, Lonning PE (2007) Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels. J Steroid Biochem Mol Biol 104(1–2):27–34
Giannarelli R, Aragona M, Coppelli A, Del PS (2003) Reducing insulin resistance with metformin: the evidence today. Diabetes Metab 29(4 Pt 2):6S28–6S35
Gingras AC, Raught B, Gygi SP et al (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15(21):2852–2864
Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE (2010) The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 152(6):346–357
Gollob MH, Green MS, Tang AS et al (2001) Identification of a gene responsible for familial Wolff–Parkinson–White syndrome. N Engl J Med 344(24):1823–1831
Graff JR, Konicek BW, Carter JH, Marcusson EG (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 68(3):631–634
Grange L, Nguyen MV, Lardy B et al (2006) NAD(P)H oxidase activity of Nox4 in chondrocytes is both inducible and involved in collagenase expression. Antioxid Redox Signal 8(9–10):1485–1496
Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (2009) Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun 380(1):98–104
Greer EL, Oskoui PR, Banko MR et al (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282(41):30107–30119
Gu Y, Zhang Y, Shi X et al (2010) Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics. Talanta 81(3):766–772
Guan S, Wang B, Li W, Guan J, Fang X (2010) Effects of berberine on expression of LOX-1 and SR-BI in human macrophage-derived foam cells induced by ox-LDL. Am J Chin Med 38(6):1161–1169
Gui SY, Wu L, Peng DY, Liu QY, Yin BP, Shen JZ (2008) Preparation and evaluation of a microemulsion for oral delivery of berberine. Pharmazie 63(7):516–519
Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH (2012) Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 68(2):213–217
Habegger KM, Hoffman NJ, Ridenour CM, Brozinick JT, Elmendorf JS (2012) AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol. Endocrinology 153(5):2130–2141
Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889
Harborne LR, Sattar N, Norman JE, Fleming R (2005) Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. J Clin Endocrinol Metab 90(8):4593–4598
Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785
Hardie DG (2011) Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc 70(1):92–99
Hariharan N, Maejima Y, Nakae J, Paik J, DePinho RA, Sadoshima J (2010) Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 107(12):1470–1482
Harrison DE, Strong R, Sharp ZD et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395
Hattori Y, Jojima T, Tomizawa A et al (2010) A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia 53(10):2256–2263
Hawley SA, Ross FA, Chevtzoff C et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11(6):554–565
Hawley SA, Fullerton MD, Ross FA et al (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336(6083):918–922
Haxhinasto S, Mathis D, Benoist C (2008) The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 205(3):565–574
He L, Sabet A, Djedjos S et al (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137(4):635–646
Hearle N, Schumacher V, Menko FH et al (2006) Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12(10):3209–3215
Hellerstein MK (1999) De novo lipogenesis in humans: metabolic and regulatory aspects. Eur J Clin Nutr 53(Suppl 1):S53–S65
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69(19):7507–7511
Holland WL, Miller RA, Wang ZV et al (2011) Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17(1):55–63
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359(15):1577–1589
Hong Y, Hui SC, Chan TY, Hou JY (2002) Effect of berberine on regression of pressure-overload induced cardiac hypertrophy in rats. Am J Chin Med 30(4):589–599
Hong Y, Hui SS, Chan BT, Hou J (2003) Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy. Life Sci 72(22):2499–2507
Hsu CC, Wahlqvist ML, Lee MS, Tsai HN (2011) Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 24(3):485–493
Hu JP, Nishishita K, Sakai E et al (2008) Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways. Eur J Pharmacol 580(1–2):70–79
Hu GX, Chen GR, Xu H, Ge RS, Lin J (2010) Activation of the AMP activated protein kinase by short-chain fatty acids is the main mechanism underlying the beneficial effect of a high fiber diet on the metabolic syndrome. Med Hypotheses 74(1):123–126
Hu PF, Chen WP, Tang JL, Bao JP, Wu LD (2011) Protective effects of berberine in an experimental rat osteoarthritis model. Phytother Res 25(6):878–885
Huang X, Wullschleger S, Shpiro N et al (2008) Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 412(2):211–221
Huisamen B, Genade S, Lochner A (2008) Signalling pathways activated by glucagon-like peptide-1 (7–36) amide in the rat heart and their role in protection against ischaemia. Cardiovasc J Afr 19(2):77–83
Ibanez L, Potau N, Ferrer A, Rodriguez-Hierro F, Marcos MV, De ZF (2002) Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational age: insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism. J Clin Endocrinol Metab 87(12):5702–5705
Iliopoulos D, Hirsch HA, Struhl K (2011) Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 71(9):3196–3201
Ishii N, Matsumura T, Kinoshita H et al (2009) Activation of AMP-activated protein kinase suppresses oxidized low-density lipoprotein-induced macrophage proliferation. J Biol Chem 284(50):34561–34569
Iwabu M, Yamauchi T, Okada-Iwabu M et al (2010) Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464(7293):1313–1319
Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104(29):12017–12022
Jakubowicz DJ, Seppala M, Jakubowicz S et al (2001) Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 86(3):1126–1133
Jalving M, Gietema JA, Lefrandt JD et al (2010) Metformin: taking away the candy for cancer? Eur J Cancer 46(13):2369–2380
Jang WG, Kim EJ, Bae IH et al (2011) Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 48(4):885–893
Jimenez-Sanchez M, Thompson F, Zavodsky E, Rubinsztein DC (2012) Autophagy and polyglutamine diseases. Prog Neurobiol 97(2):67–82
Jiralerspong S, Palla SL, Giordano SH et al (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297–3302
Johnson JB, Laub DR, John S (2006) The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life. Med Hypotheses 67(2):209–211
Johnson JB, Summer W, Cutler RG et al (2007) Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med 42(5):665–674
Johnston CS, White AM, Kent SM (2009) Preliminary evidence that regular vinegar ingestion favorably influences hemoglobin A1c values in individuals with type 2 diabetes mellitus. Diabetes Res Clin Pract 84(2):e15–e17
Johnston CS, Steplewska I, Long CA, Harris LN, Ryals RH (2010) Examination of the antiglycemic properties of vinegar in healthy adults. Ann Nutr Metab 56(1):74–79
Jones RG, Plas DR, Kubek S et al (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18(3):283–293
Julius U (2003) Influence of plasma free fatty acids on lipoprotein synthesis and diabetic dyslipidemia. Exp Clin Endocrinol Diabetes 111(5):246–250
Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Sugimoto T (2008) Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression. Biochem Biophys Res Commun 375(3):414–419
Kang KY, Kim YK, Yi H et al (2013) Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol 16(1):85–92
Kim YD, Park KG, Lee YS et al (2008) Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 57(2):306–314
Kimura T, Tomura H, Sato K et al (2010) Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells. J Biol Chem 285(7):4387–4397
Kirpichnikov D, McFarlane SI, Sowers JR (2002) Metformin: an update. Ann Intern Med 137(1):25–33
Kisfalvi K, Rey O, Young SH, Sinnett-Smith J, Rozengurt E (2007) Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq protein-coupled receptor agonists through an mTOR-dependent pathway. Endocrinology 148(7):3246–3257
Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E (2009) Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res 69(16):6539–6545
Knowler WC, Barrett-Connor E, Fowler SE et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346(6):393–403
Kondo T, Kishi M, Fushimi T, Ugajin S, Kaga T (2009a) Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects. Biosci Biotechnol Biochem 73(8):1837–1843
Kondo T, Kishi M, Fushimi T, Kaga T (2009b) Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem 57(13):5982–5986
Kong W, Wei J, Abidi P et al (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10(12):1344–1351
Kong WJ, Wei J, Zuo ZY et al (2008) Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism 57(8):1029–1037
Koo SH, Flechner L, Qi L et al (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437(7062):1109–1111
Kukidome D, Nishikawa T, Sonoda K et al (2006) Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55(1):120–127
Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ (2010) Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33(2):322–326
Lee WJ, Song KH, Koh EH et al (2005) Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 332(3):885–891
Lee YS, Kim WS, Kim KH et al (2006) Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55(8):2256–2264
Lee TS, Pan CC, Peng CC et al (2010a) Anti-atherogenic effect of berberine on LXRalpha-ABCA1-dependent cholesterol efflux in macrophages. J Cell Biochem 111(1):104–110
Lee JM, Seo WY, Song KH et al (2010b) AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner. J Biol Chem 285(42):32182–32191
Lee YS, Kim YS, Lee SY et al (2010c) AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts. Bone 47(5):926–937
Lee IA, Hyun YJ, Kim DH (2010d) Berberine ameliorates TNBS-induced colitis by inhibiting lipid peroxidation, enterobacterial growth and NF-kappaB activation. Eur J Pharmacol 648(1–3):162–170
Lee CG, Boyko EJ, Barrett-Connor E et al (2011) Insulin sensitizers may attenuate lean mass loss in older men with diabetes. Diabetes Care 34(11):2381–2386
Lee JH, Kim TI, Jeon SM, Hong SP, Cheon JH, Kim WH (2012) The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer 131(3):751–759
Leonhardt M, Langhans W (2004) Fatty acid oxidation and control of food intake. Physiol Behav 83(4):645–651
Lesniewski LA, Durrant JR, Connell ML, Folian BJ, Donato AJ, Seals DR (2011) Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation. J Gerontol A Biol Sci Med Sci 66(4):409–418
Li H, Miyahara T, Tezuka Y et al (1999) The effect of kampo formulae on bone resorption in vitro and in vivo. II. Detailed study of berberine. Biol Pharm Bull 22(4):391–396
Li F, Wang HD, Lu DX et al (2006) Neutral sulfate berberine modulates cytokine secretion and increases survival in endotoxemic mice. Acta Pharmacol Sin 27(9):1199–1205
Li HL, Yin R, Chen D et al (2007) Long-term activation of adenosine monophosphate-activated protein kinase attenuates pressure-overload-induced cardiac hypertrophy. J Cell Biochem 100(5):1086–1099
Li K, Yao W, Zheng X, Liao K (2009) Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage. Cell Res 19(8):1006–1017
Li D, Wang D, Wang Y, Ling W, Feng X, Xia M (2010a) Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice. J Biol Chem 285(43):33499–33509
Li J, Benashski SE, Venna VR, McCullough LD (2010b) Effects of metformin in experimental stroke. Stroke 41(11):2645–2652
Li Y, Xu S, Mihaylova MM et al (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13(4):376–388
Li X, Chen H, Guan Y et al (2013) Acetic acid activates the AMP-activated protein kinase signaling pathway to regulate lipid metabolism in bovine hepatocytes. PLoS ONE 8(7):e67880
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32(9):1620–1625
Linker K, Pautz A, Fechir M, Hubrich T, Greeve J, Kleinert H (2005) Involvement of KSRP in the post-transcriptional regulation of human iNOS expression-complex interplay of KSRP with TTP and HuR. Nucleic Acids Res 33(15):4813–4827
Liu LZ, Cheung SC, Lan LL et al (2010) Berberine modulates insulin signaling transduction in insulin-resistant cells. Mol Cell Endocrinol 317(1–2):148–153
Lo YY, Conquer JA, Grinstein S, Cruz TF (1998) Interleukin-1 beta induction of c-fos and collagenase expression in articular chondrocytes: involvement of reactive oxygen species. J Cell Biochem 69(1):19–29
Lu J, McKinsey TA, Zhang CL, Olson EN (2000) Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6(2):233–244
Lu DY, Tang CH, Chen YH, Wei IH (2010) Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem 110(3):697–705
Luque-Ramirez M, Escobar-Morreale HF (2010) Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations. Horm Metab Res 42(11):815–820
Ma X, Jiang Y, Wu A et al (2010) Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice. PLoS ONE 5(10):e13489
Mai QG, Zhang ZM, Xu S et al (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112(10):2902–2909
Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW, Sonenberg N (2004) eIF4E—from translation to transformation. Oncogene 23(18):3172–3179
Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem 280(45):37377–37382
Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM (2005) Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111(5):583–590
Massion PB, Balligand JL (2007) Relevance of nitric oxide for myocardial remodeling. Curr Heart Fail Rep 4(1):18–25
McCarty MF (2001a) Hepatothermic therapy of obesity: rationale and an inventory of resources. Med Hypotheses 57(3):324–336
McCarty MF (2001b) Does regular ethanol consumption promote insulin sensitivity and leanness by stimulating AMP-activated protein kinase? Med Hypotheses 57(3):405–407
McCarty MF (2004) Chronic activation of AMP-activated kinase as a strategy for slowing aging. Med Hypotheses 63(2):334–339
McCarty MF (2005) High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy. Med Hypotheses 64(6):1216–1219
McCarty MF (2010) Salsalate may have broad utility in the prevention and treatment of vascular disorders and the metabolic syndrome. Med Hypotheses 75(3):276–281
McCarty MF (2011) mTORC1 activity as a determinant of cancer risk—rationalizing the cancer-preventive effects of adiponectin, metformin, rapamycin, and low-protein vegan diets. Med Hypotheses 77(4):642–648
McCarty MF (2013) Could carbohydrate-concentrated diets mimic calorie restriction in slowing the aging process? Available at: http://catalyticlongevity.org/prepub_archive/Slabber-essay.pdf
McCarty MF, Block KI (2006) Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integr Cancer Ther 5(3):252–268
McCarty MF, Barroso-Aranda J, Contreras F (2009) AMP-activated kinase may suppress NADPH oxidase activation in vascular tissues. Med Hypotheses 72(4):468–470
McFate T, Mohyeldin A, Lu H et al (2008) Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 283(33):22700–22708
McGarry JD, Leatherman GF, Foster DW (1978) Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem 253(12):4128–4136
McGee SL, van Denderen BJ, Howlett KF et al (2008) AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57(4):860–867
Mehenni H, Gehrig C, Nezu J et al (1998) Loss of LKB1 kinase activity in Peutz–Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet 63(6):1641–1650
Meneghini LF, Orozco-Beltran D, Khunti K et al (2011) Weight beneficial treatments for type 2 diabetes. J Clin Endocrinol Metab 96(11):3337–3353
Michalek RD, Gerriets VA, Jacobs SR et al (2011) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186(6):3299–3303
Micic D, Cvijovic G, Trajkovic V, Duntas LH, Polovina S (2011) Metformin: its emerging role in oncology. Hormones (Athens) 10(1):5–15
Mihaylova MM, Vasquez DS, Ravnskjaer K et al (2011) Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145(4):607–621
Min SW, Cho SH, Zhou Y et al (2010) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67(6):953–966
Monsuez JJ, Gesquiere-Dando A, Rivera S (2011) Cardiovascular prevention of cognitive decline. Cardiol Res Pract 2011:250970
Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL (2011) Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology 152(11):4610–4619
Muoio DM, Seefeld K, Witters LA, Coleman RA (1999) 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 338(Pt 3):783–791
Musi N, Goodyear LJ (2003) AMP-activated protein kinase and muscle glucose uptake. Acta Physiol Scand 178(4):337–345
Musi N, Hirshman MF, Nygren J et al (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51(7):2074–2081
Nath N, Giri S, Prasad R, Salem ML, Singh AK, Singh I (2005) 5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J Immunol 175(1):566–574
Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S (2009a) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 182(12):8005–8014
Nath N, Khan M, Rattan R et al (2009b) Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity. Biochem Biophys Res Commun 386(1):16–20
Nieuwenhuis-Ruifrok AE, Kuchenbecker WK, Hoek A, Middleton P, Norman RJ (2009) Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis. Hum Reprod Update 15(1):57–68
Oliveira SM, Ehtisham J, Redwood CS, Ostman-Smith I, Blair EM, Watkins H (2003) Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. J Mol Cell Cardiol 35(10):1251–1255
Olmos Y, Valle I, Borniquel S et al (2009) Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes. J Biol Chem 284(21):14476–14484
Ostman E, Granfeldt Y, Persson L, Bjorck I (2005) Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr 59(9):983–988
Park H, Kaushik VK, Constant S et al (2002) Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J Biol Chem 277(36):32571–32577
Pearson KJ, Baur JA, Lewis KN et al (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8(2):157–168
Pelletier JP, DiBattista JA, Roughley P, McCollum R, Martel-Pelletier J (1993) Cytokines and inflammation in cartilage degradation. Rheum Dis Clin North Am 19(3):545–568
Pelletier JP, Jovanovic D, Fernandes JC et al (1998) Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum 41(7):1275–1286
Pelletier JP, Lascau-Coman V, Jovanovic D et al (1999) Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors. J Rheumatol 26(9):2002–2014
Peng L, Li ZR, Green RS, Holzman IR, Lin J (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139(9):1619–1625
Phillips LK, Prins JB (2008) The link between abdominal obesity and the metabolic syndrome. Curr Hypertens Rep 10(2):156–164
Phillips SA, Ciaraldi TP, Kong AP et al (2003) Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy. Diabetes 52(3):667–674
Pierce GL, Lesniewski LA, Lawson BR, Beske SD, Seals DR (2009) Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation 119(9):1284–1292
Piwkowska A, Rogacka D, Jankowski M, Dominiczak MH, Stepinski JK, Angielski S (2010) Metformin induces suppression of NAD(P)H oxidase activity in podocytes. Biochem Biophys Res Commun 393(2):268–273
Poulsen MM, Vestergaard PF, Clasen BF et al (2013) High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 62(4):1186–1195
Praharaj SK, Jana AK, Goyal N, Sinha VK (2011) Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis. Br J Clin Pharmacol 71(3):377–382
Puyal J, Ginet V, Grishchuk Y, Truttmann AC, Clarke PG (2011) Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders. Neuroscientist 18(3):224–236
Qin X, Guo BT, Wan B et al (2010) Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine. J Immunol 185(3):1855–1863
Rasouli N, Molavi B, Elbein SC, Kern PA (2007) Ectopic fat accumulation and metabolic syndrome. Diabetes Obes Metab 9(1):1–10
Rejnmark L (2008) Bone effects of glitazones and other anti-diabetic drugs. Curr Drug Saf 3(3):194–198
Rodriguez-Moctezuma JR, Robles-Lopez G, Lopez-Carmona JM, Gutierrez-Rosas MJ (2005) Effects of metformin on the body composition in subjects with risk factors for type 2 diabetes. Diabetes Obes Metab 7(2):189–192
Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (2010) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377(9759):31–41
Roussel R, Travert F, Pasquet B et al (2010) Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 170(21):1892–1899
Rozengurt E, Sinnett-Smith J, Kisfalvi K (2010) Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer Res 16(9):2505–2511
Sakakibara S, Yamauchi T, Oshima Y, Tsukamoto Y, Kadowaki T (2006) Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. Biochem Biophys Res Commun 344(2):597–604
Sakakibara S, Murakami R, Takahashi M et al (2010) Vinegar intake enhances flow-mediated vasodilatation via upregulation of endothelial nitric oxide synthase activity. Biosci Biotechnol Biochem 74(5):1055–1061
Salminen A, Hyttinen JM, Kaarniranta K (2011a) AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl) 89(7):667–676
Salminen A, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M (2011b) AMP-activated protein kinase: a potential player in Alzheimer's disease. J Neurochem 118(4):460–474
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 4, CD002967
Samuels A, Perry MJ, Gibson RL, Colley S, Tobias JH (2001) Role of endothelial nitric oxide synthase in estrogen-induced osteogenesis. Bone 29(1):24–29
Sanchez AM, Candau RB, Csibi A, Pagano AF, Raibon A, Bernardi H (2012) The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis. Am J Physiol Cell Physiol 303(5):C475–C485
Sanli T, Rashid A, Liu C et al (2010) Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys 78(1):221–229
Scarpello JH (2003) Improving survival with metformin: the evidence base today. Diabetes Metab 29(4 Pt 2):6S36–6S43
Scharrer E (1999) Control of food intake by fatty acid oxidation and ketogenesis. Nutrition 15(9):704–714
Scheen AJ (1996) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30(5):359–371
Schramm TK, Gislason GH, Vaag A et al (2011) Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 32(15):1900–1908
Selman C, Tullet JM, Wieser D et al (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326(5949):140–144
Semenza GL (2007) HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 39(3):231–234
Sengupta S, Jang BC, Wu MT, Paik JH, Furneaux H, Hla T (2003) The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem 278(27):25227–25233
Sharma PK, Bhansali A, Sialy R, Malhotra S, Pandhi P (2006) Effects of pioglitazone and metformin on plasma adiponectin in newly detected type 2 diabetes mellitus. Clin Endocrinol (Oxf) 65(6):722–728
Shaw RJ (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 196(1):65–80
Simpson ER, Misso M, Hewitt KN et al (2005) Estrogen—the good, the bad, and the unexpected. Endocr Rev 26(3):322–330
Smith MR, Jaramillo M, Liu YL et al (1990) Translation initiation factors induce DNA synthesis and transform NIH 3 T3 cells. New Biol 2(7):648–654
Smith AR, Visioli F, Frei B, Hagen TM (2008) Lipoic acid significantly restores, in rats, the age-related decline in vasomotion. Br J Pharmacol 153(8):1615–1622
Smith DL Jr, Elam CF Jr, Mattison JA et al (2010) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 65(5):468–474
Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9(1):59–71
St-Onge MP, Jones PJ (2002) Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity. J Nutr 132(3):329–332
Sumarac-Dumanovic M, Jeremic D, Pantovic A et al (2013) Therapeutic improvement of glucoregulation in newly diagnosed type 2 diabetes patients is associated with a reduction of IL-17 levels. Immunobiology 218(8):1113–1118
Sun Y, Xun K, Wang Y, Chen X (2009) A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs 20(9):757–769
Tan BX, Yao WX, Ge J et al (2011) Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer 117(22):5103–5111
Tang J, Feng Y, Tsao S, Wang N, Curtain R, Wang Y (2009) Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmacol 126(1):5–17
Tang Y, Chen Y, Jiang H, Nie D (2011) The role of short-chain fatty acids in orchestrating two types of programmed cell death in colon cancer. Autophagy 7(2):235–237
Tarkun I, Dikmen E, Cetinarslan B, Canturk Z (2010) Impact of treatment with metformin on adipokines in patients with polycystic ovary syndrome. Eur Cytokine Netw 21(4):272–277
Terkeltaub R, Yang B, Lotz M, Liu-Bryan R (2011) Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1beta and tumor necrosis factor alpha. Arthritis Rheum 63(7):1928–1937
Thomas GV, Tran C, Mellinghoff IK et al (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12(1):122–127
Thornton C, Bright NJ, Sastre M, Muckett PJ, Carling D (2011) AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J 434(3):503–512
Timmers S, Konings E, Bilet L et al (2011) Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 14:612–622
Turban S, Stretton C, Drouin O et al (2012) Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. J Biol Chem 287(24):20088–20099
Turner N, Li JY, Gosby A et al (2008) Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 57(5):1414–1418
Tzoulaki I, Molokhia M, Curcin V et al (2009) Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 339:b4731
UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352(9131):854–865
Um JH, Park SJ, Kang H et al (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59(3):554–563
Unger RH, Clark GO, Scherer PE, Orci L (2010) Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801(3):209–214
Varady KA, Hellerstein MK (2007) Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am J Clin Nutr 86(1):7–13
Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del BS, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial–mesenchymal transition (EMT) status. Cell Cycle 9(18):3807–3814
Vazquez-Martin A, Oliveras-Ferraros C, Del BS, Martin-Castillo B, Menendez JA (2011) The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 126(2):355–364
Vestergaard P, Rejnmark L, Mosekilde L (2005) Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 48(7):1292–1299
Viana R, Aguado C, Esteban I et al (2008) Role of AMP-activated protein kinase in autophagy and proteasome function. Biochem Biophys Res Commun 369(3):964–968
Villanueva-Penacarrillo ML, Martin-Duce A, Ramos-Alvarez I et al (2011) Characteristic of GLP-1 effects on glucose metabolism in human skeletal muscle from obese patients. Regul Pept 168(1–3):39–44
Vingtdeux V, Giliberto L, Zhao H et al (2010) AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem 285(12):9100–9113
Vingtdeux V, Chandakkar P, Zhao H, d’Abramo C, Davies P, Marambaud P (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J 25(1):219–231
Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK (2004) High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32(12):1377–1382
Wang W, Fan J, Yang X et al (2002) AMP-activated kinase regulates cytoplasmic HuR. Mol Cell Biol 22(10):3425–3436
Wang W, Yang X, Kawai T et al (2004) AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR. J Biol Chem 279(46):48376–48388
Wang S, Xu J, Song P, Viollet B, Zou MH (2009) In vivo activation of AMP-activated protein kinase attenuates diabetes-enhanced degradation of GTP cyclohydrolase I. Diabetes 58(8):1893–1901
Wang S, Zhang M, Liang B et al (2010) AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res 106(6):1117–1128
Watt MJ, Holmes AG, Pinnamaneni SK et al (2006) Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 290(3):E500–E508
Wei W, Zhao H, Wang A et al (2012) A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol 166(1):99–105
Wijkander J, Landstrom TR, Manganiello V, Belfrage P, Degerman E (1998) Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70 S6 kinase. Endocrinology 139(1):219–227
Won JS, Im YB, Kim J, Singh AK, Singh I (2010) Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem Biophys Res Commun 399(4):487–491
Wright JL, Stanford JL (2009) Metformin use and prostate cancer in Caucasian men: results from a population-based case–control study. Cancer Causes Control 20(9):1617–1622
Wu Y, Song P, Xu J, Zhang M, Zou MH (2007) Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem 282(13):9777–9788
Xia X, Yan J, Shen Y et al (2011) Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS ONE 6(2):e16556
Xiao B, Sanders MJ, Underwood E et al (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472(7342):230–233
Xie Z, Zhang J, Wu J, Viollet B, Zou MH (2008) Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes 57(12):3222–3230
Xilouri M, Stefanis L (2010) Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 9(6):701–719
Yap F, Craddock L, Yang J (2011) Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription. Int J Biol Sci 7(5):645–650
Yeung F, Hoberg JE, Ramsey CS et al (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23(12):2369–2380
Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396(6706):77–80
Yoshino J, Conte C, Fontana L et al (2012) Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab 16(5):658–664
Young A, Wu W, Sun W et al (2009) Flow activation of AMP-activated protein kinase in vascular endothelium leads to Kruppel-like factor 2 expression. Arterioscler Thromb Vasc Biol 29(11):1902–1908
Yu Y, Liu L, Wang X et al (2010) Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. Biochem Pharmacol 79(7):1000–1006
Zeng X, Zeng X (1999) Relationship between the clinical effects of berberine on severe congestive heart failure and its concentration in plasma studied by HPLC. Biomed Chromatogr 13(7):442–444
Zeng XH, Zeng XJ, Li YY (2003) Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 92(2):173–176
Zhang Y, Lee TS, Kolb EM et al (2006) AMP-activated protein kinase is involved in endothelial NO synthase activation in response to shear stress. Arterioscler Thromb Vasc Biol 26(6):1281–1287
Zhang Y, Li X, Zou D et al (2008a) Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab 93(7):2559–2565
Zhang P, Hu X, Xu X et al (2008b) AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52(5):918–924
Zhang CX, Pan SN, Meng RS et al (2011a) Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats. Clin Exp Pharmacol Physiol 38(1):55–62
Zhang ZJ, Zheng ZJ, Kan H et al (2011b) Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care 34(10):2323–2328
Zhou H, Mineshita S (2000) The effect of berberine chloride on experimental colitis in rats in vivo and in vitro. J Pharmacol Exp Ther 294(3):822–829
Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174
Zhou J, Zhou S, Tang J et al (2009) Protective effect of berberine on beta cells in streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats. Eur J Pharmacol 606(1–3):262–268
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McCarty, M.F. AMPK activation—protean potential for boosting healthspan. AGE 36, 641–663 (2014). https://doi.org/10.1007/s11357-013-9595-y
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DOI: https://doi.org/10.1007/s11357-013-9595-y