Skip to main content
SpringerLink
Log in

AMP-Activated Protein Kinase and Metabolic Control

  • Chapter
  • First Online:
Diabetes - Perspectives in Drug Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 203))

Abstract

AMP-activated protein kinase (AMPK ), a phylogenetically conserved serine/threonine protein kinase, is a major regulator of cellular and whole-body energy homeostasis that coordinates metabolic pathways in order to balance nutrient supply with energy demand. It is now recognized that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile, and blood pressure in insulin-resistant rodents. Indeed, AMPK activation mimics the beneficial effects of physical activity or those of calorie restriction by acting on multiple cellular targets. In addition, it is now demonstrated that AMPK is one of the probable (albeit indirect) targets of major antidiabetic drugs including the biguanides (metformin ) and thiazolidinedione s, as well as of insulin-sensitizing adipokines (e.g., adiponectin ). Taken together, such findings highlight the logic underlying the concept of targeting the AMPK pathway for the treatment of metabolic syndrome and type 2 diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alberti KG, Zimmet PZ (1998) New diagnostic criteria and classification of diabetes–again? Diabet Med 15:535–536

    Google Scholar 

  • Andersson U, Filipsson K et al (2004) AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279:12005–12008

    CAS  PubMed  Google Scholar 

  • Andreelli F, Foretz M et al (2006) Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology 147:2432–2441

    CAS  PubMed  Google Scholar 

  • Anthonsen MW, Ronnstrand L et al (1998) Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J Biol Chem 273:215–221

    CAS  PubMed  Google Scholar 

  • Assifi MM, Suchankova G et al (2005) AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats. Am J Physiol Endocrinol Metab 289:E794–E800

    CAS  PubMed  Google Scholar 

  • Banerjee RR, Rangwala SM et al (2004) Regulation of fasted blood glucose by resistin. Science 303:1195–1198

    CAS  PubMed  Google Scholar 

  • Banks AS, Kon N et al (2008) SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8:333–341

    PubMed Central  CAS  PubMed  Google Scholar 

  • Barnes BR, Marklund S et al (2004) The 5′-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. J Biol Chem 279:38441–38447

    CAS  PubMed  Google Scholar 

  • Baur JA, Pearson KJ et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    CAS  PubMed  Google Scholar 

  • Bergeron R, Russell RR 3rd et al (1999) Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol 276:E938–E944

    CAS  PubMed  Google Scholar 

  • Bergeron R, Previs SF et al (2001a) Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50:1076–1082

    CAS  PubMed  Google Scholar 

  • Bergeron R, Ren JM et al (2001b) Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 281:E1340–E1346

    CAS  PubMed  Google Scholar 

  • Boon H, Bosselaar M et al (2008) Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia 51:1893–1900

    CAS  PubMed  Google Scholar 

  • Bordone L, Motta MC et al (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4:e31

    PubMed Central  PubMed  Google Scholar 

  • Bruce CR, Mertz VA et al (2005) The stimulatory effect of globular adiponectin on insulin-stimulated glucose uptake and fatty acid oxidation is impaired in skeletal muscle from obese subjects. Diabetes 54:3154–3160

    CAS  PubMed  Google Scholar 

  • Buhl ES, Jessen N et al (2002) Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 51:2199–2206

    CAS  PubMed  Google Scholar 

  • Butler AE, Janson J et al (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    CAS  PubMed  Google Scholar 

  • Canto C, Gerhart-Hines Z et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458:1056–1060

    PubMed Central  CAS  PubMed  Google Scholar 

  • Canto C, Jiang LQ et al (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11:213–219

    PubMed Central  CAS  PubMed  Google Scholar 

  • Carattino MD, Edinger RS et al (2005) Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells. J Biol Chem 280:17608–17616

    CAS  PubMed  Google Scholar 

  • Carey DG, Cowin GJ et al (2002) Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients [corrected]. Obes Res 10:1008–1015

    CAS  PubMed  Google Scholar 

  • Carey AL, Steinberg GR et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase . Diabetes 55:2688–2697

    CAS  PubMed  Google Scholar 

  • Chen ZP, Mitchelhill KI et al (1999) AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 443:285–289

    CAS  PubMed  Google Scholar 

  • Chen ZP, McConell GK et al (2000) AMPK signaling in contracting human skeletal muscle: acetyl-CoA carboxylase and NO synthase phosphorylation. Am J Physiol Endocrinol Metab 279:E1202–E1206

    CAS  PubMed  Google Scholar 

  • Chen Z, Peng IC et al (2009) AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res 104:496–505

    PubMed Central  CAS  PubMed  Google Scholar 

  • Clarke PR, Hardie DG (1990) 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 9:2439–2446

    PubMed Central  CAS  PubMed  Google Scholar 

  • Collins QF, Liu HY et al (2007) Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5′-AMP-activated protein kinase . J Biol Chem 282:30143–30149

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cool B, Zinker B 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 3:403–416

    CAS  PubMed  Google Scholar 

  • Corton JM, Gillespie JG et al (1995) 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229:558–565

    CAS  PubMed  Google Scholar 

  • da Silva Xavier G, Leclerc I et al (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371:761–774

    PubMed Central  PubMed  Google Scholar 

  • Dasgupta B, Milbrandt J (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 104:7217–7222

    PubMed Central  CAS  PubMed  Google Scholar 

  • Daval M, Diot-Dupuy F et al (2005) Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J Biol Chem 280:25250–25257

    CAS  PubMed  Google Scholar 

  • Davis BJ, Xie Z et al (2006) Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase . Diabetes 55:496–505

    CAS  PubMed  Google Scholar 

  • DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(Suppl 2):S157–S163

    PubMed Central  CAS  PubMed  Google Scholar 

  • Donath MY, Ehses JA et al (2005) Mechanisms of beta-cell death in type 2 diabetes. Diabetes 54(Suppl 2):S108–S113

    CAS  PubMed  Google Scholar 

  • Dreyer HC, Drummond MJ et al (2008) Resistance exercise increases human skeletal muscle AS160/TBC1D4 phosphorylation in association with enhanced leg glucose uptake during postexercise recovery. J Appl Physiol 105:1967–1974

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dyck JR, Lopaschuk GD (2006) AMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol 574:95–112

    PubMed Central  CAS  PubMed  Google Scholar 

  • Eckel RH, Grundy SM et al (2005) The metabolic syndrome. Lancet 365:1415–1428

    CAS  PubMed  Google Scholar 

  • El-Assaad W, Buteau J et al (2003) Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 144:4154–4163

    CAS  PubMed  Google Scholar 

  • Eto K, Yamashita T et al (2002) Genetic manipulations of fatty acid metabolism in beta-cells are associated with dysregulated insulin secretion. Diabetes 51(Suppl 3):S414–S420

    CAS  PubMed  Google Scholar 

  • Evans AM, Mustard KJ et al (2005) Does AMP-activated protein kinase couple inhibition of mitochondrial oxidative phosphorylation by hypoxia to calcium signaling in O2-sensing cells? J Biol Chem 280:41504–41511

    CAS  PubMed  Google Scholar 

  • Febbraio MA, Pedersen BK (2005) Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33:114–119

    PubMed  Google Scholar 

  • Fisher JS, Gao J et al (2002) Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab 282:E18–E23

    CAS  PubMed  Google Scholar 

  • Fonseca VA (2009) Defining and characterizing the progression of type 2 diabetes. Diabetes Care 32(Suppl 2):S151–S156

    PubMed Central  PubMed  Google Scholar 

  • Foretz M, Carling D et al (1998) AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes. J Biol Chem 273:14767–14771

    CAS  PubMed  Google Scholar 

  • Foretz M, Ancellin N 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 54:1331–1339

    CAS  PubMed  Google Scholar 

  • Fraser SA, Mount PF et al (2003) Inhibition of the Na-K-2Cl cotransporter by novel interaction with the metabolic sensor AMP-activated protein kinase . J Am Soc Nephrol 14:545A

    Google Scholar 

  • Fryer LG, Parbu-Patel A et al (2002) The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226–25232

    CAS  PubMed  Google Scholar 

  • Fujii N, Ho RC et al (2008) Ablation of AMP-activated protein kinase alpha2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes 57:2958–2966

    PubMed Central  CAS  PubMed  Google Scholar 

  • Garton AJ, Yeaman SJ (1990) Identification and role of the basal phosphorylation site on hormone-sensitive lipase. Eur J Biochem 191:245–250

    CAS  PubMed  Google Scholar 

  • Garton AJ, Campbell DG et al (1989) Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase . A possible antilipolytic mechanism. Eur J Biochem 179:249–254

    CAS  PubMed  Google Scholar 

  • Gledhill JR, Montgomery MG et al (2007) Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci USA 104:13632–13637

    PubMed Central  CAS  PubMed  Google Scholar 

  • Glund S, Deshmukh A et al (2007) Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes 56:1630–1637

    CAS  PubMed  Google Scholar 

  • Glund S, Treebak JT et al (2009) Role of adenosine 5'-monophosphate-activated protein kinase in interleukin-6 release from isolated mouse skeletal muscle. Endocrinology 150:600–606

    CAS  PubMed  Google Scholar 

  • Hammer S, Snel M et al (2008) Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. J Am Coll Cardiol 52:1006–1012

    CAS  PubMed  Google Scholar 

  • Hayashi T, Hirshman MF et al (1998) Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47:1369–1373

    CAS  PubMed  Google Scholar 

  • Higa M, Zhou YT et al (1999) Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc Natl Acad Sci USA 96:11513–11518

    PubMed Central  CAS  PubMed  Google Scholar 

  • Holmes BF, Kurth-Kraczek EJ et al (1999) Chronic activation of 5′-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 87:1990–1995

    CAS  PubMed  Google Scholar 

  • Holmes BF, Lang DB et al (2004) AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle. Am J Physiol Endocrinol Metab 287:E739–E743

    CAS  PubMed  Google Scholar 

  • Hou X, Xu S et al (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase . J Biol Chem 283:20015–20026

    PubMed Central  CAS  PubMed  Google Scholar 

  • Howitz KT, Bitterman KJ et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    CAS  PubMed  Google Scholar 

  • Iglesias MA, Ye JM et al (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51:2886–2894

    CAS  PubMed  Google Scholar 

  • Jager S, Handschin C et al (2007) AMP-activated protein kinase (AMPK ) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104:12017–12022

    PubMed Central  PubMed  Google Scholar 

  • Jazet IM, Schaart G et al (2008) Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients. Diabetologia 51:309–319

    CAS  PubMed  Google Scholar 

  • Jorgensen SB, Wojtaszewski JF et al (2005) Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J 19:1146–1148

    PubMed  Google Scholar 

  • Kahn SE, Hull RL et al (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846

    CAS  PubMed  Google Scholar 

  • Kaiser N, Leibowitz G et al (2003) Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J Pediatr Endocrinol Metab 16:5–22

    CAS  PubMed  Google Scholar 

  • Kamohara S, Burcelin R et al (1997) Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389:374–377

    CAS  PubMed  Google Scholar 

  • Katsuki A, Sumida Y et al (2003) Increased visceral fat and serum levels of triglyceride are associated with insulin resistance in Japanese metabolically obese, normal weight subjects with normal glucose tolerance. Diabetes Care 26:2341–2344

    CAS  PubMed  Google Scholar 

  • Kefas BA, Cai Y et al (2003a) AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase. J Mol Endocrinol 30:151–161

    CAS  PubMed  Google Scholar 

  • Kefas BA, Heimberg H et al (2003b) AICA-riboside induces apoptosis of pancreatic beta cells through stimulation of AMP-activated protein kinase . Diabetologia 46:250–254

    CAS  PubMed  Google Scholar 

  • Kelly M, Keller C et al (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320:449–454

    CAS  PubMed  Google Scholar 

  • Kim MS, Park JY et al (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase . Nat Med 10:727–733

    CAS  PubMed  Google Scholar 

  • Kim WH, Lee JW et al (2007) AICAR potentiates ROS production induced by chronic high glucose: roles of AMPK in pancreatic beta-cell apoptosis. Cell Signal 19:791–805

    CAS  PubMed  Google Scholar 

  • Knowler WC, Barrett-Connor E et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin . N Engl J Med 346:393–403

    CAS  PubMed  Google Scholar 

  • Koistinen HA, Galuska D et al (2003) 5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes 52:1066–1072

    CAS  PubMed  Google Scholar 

  • Kola B, Hubina E et al (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase . J Biol Chem 280:25196–25201

    CAS  PubMed  Google Scholar 

  • Koo SH, Flechner L et al (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437:1109–1111

    CAS  PubMed  Google Scholar 

  • Kubota N, Terauchi Y et al (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866

    CAS  PubMed  Google Scholar 

  • Kurth-Kraczek EJ, Hirshman MF et al (1999) 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48:1667–1671

    CAS  PubMed  Google Scholar 

  • Lagouge M, Argmann C et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122

    CAS  PubMed  Google Scholar 

  • Lan F, Cacicedo JM et al (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1 . Possible role in AMP-activated protein kinase activation. J Biol Chem 283:27628–27635

    PubMed Central  CAS  PubMed  Google Scholar 

  • Larson-Meyer DE, Heilbronn LK et al (2006) Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29:1337–1344

    PubMed Central  PubMed  Google Scholar 

  • Lau KS, Grange RW et al (2000) nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol Genomics 2:21–27

    CAS  PubMed  Google Scholar 

  • Leclerc I, Kahn A et al (1998) The 5′-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex. FEBS Lett 431:180–184

    CAS  PubMed  Google Scholar 

  • Leclerc I, Lenzner C et al (2001) Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase . Diabetes 50:1515–1521

    CAS  PubMed  Google Scholar 

  • Leclerc I, Woltersdorf WW et al (2004) Metformin, but not leptin , regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab 286:E1023–E1031

    CAS  PubMed  Google Scholar 

  • Lee WJ, Lee IK et al (2005a) Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase . Arterioscler Thromb Vasc Biol 25:2488–2494

    CAS  PubMed  Google Scholar 

  • Lee WJ, Song KH et al (2005b) Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 332:885–891

    CAS  PubMed  Google Scholar 

  • Lee-Young RS, Griffee SR et al (2009) Skeletal muscle AMP-activated protein kinase is essential for the metabolic response to exercise in vivo. J Biol Chem 284:23925–23934

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lee-Young RS, Ayala JE et al (2010) Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. Am J Physiol Regul Integr Comp Physiol 298:R1399–R1408

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liao Y, Takashima S et al (2005) Exacerbation of heart failure in adiponectin -deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc Res 67:705–713

    CAS  PubMed  Google Scholar 

  • Lihn AS, Jessen N et al (2004) AICAR stimulates adiponectin and inhibits cytokines in adipose tissue. Biochem Biophys Res Commun 316:853–858

    CAS  PubMed  Google Scholar 

  • Lin HZ, Yang SQ et al (2000) Metformin reverses fatty liver disease in obese, leptin -deficient mice. Nat Med 6:998–1003

    CAS  PubMed  Google Scholar 

  • Lira VA, Soltow QA et al (2007) Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. Am J Physiol Endocrinol Metab 293:E1062–E1068

    CAS  PubMed  Google Scholar 

  • Lochhead PA, Salt IP et al (2000) 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49:896–903

    CAS  PubMed  Google Scholar 

  • Luo Z, Saha AK et al (2005) AMPK , the metabolic syndrome and cancer. Trends Pharmacol Sci 26:69–76

    CAS  PubMed  Google Scholar 

  • Lupi R, Del Guerra S et al (2002) Lipotoxicity in human pancreatic islets and the protective effect of metformin . Diabetes 51(Suppl 1):S134–S137

    CAS  PubMed  Google Scholar 

  • Maeda N, Takahashi M et al (2001) PPARgamma ligands increase expression and plasma concentrations of adiponectin , an adipose-derived protein. Diabetes 50:2094–2099

    CAS  PubMed  Google Scholar 

  • Majithiya JB, Balaraman R (2006) Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats. Life Sci 78:2615–2624

    CAS  PubMed  Google Scholar 

  • Martin TL, Alquier T et al (2006) Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J Biol Chem 281:18933–18941

    CAS  PubMed  Google Scholar 

  • Matejkova O, Mustard KJ et al (2004) Possible involvement of AMP-activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat. FEBS Lett 569:245–248

    CAS  PubMed  Google Scholar 

  • Maxwell AJ, Schauble E et al (1998) Limb blood flow during exercise is dependent on nitric oxide. Circulation 98:369–374

    CAS  PubMed  Google Scholar 

  • Merrill GF, Kurth EJ et al (1997) AICA riboside increases AMP-activated protein kinase , fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 273:E1107–E1112

    CAS  PubMed  Google Scholar 

  • Michael LF, Wu Z et al (2001) Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 98:3820–3825

    PubMed Central  CAS  PubMed  Google Scholar 

  • Milne JC, Lambert PD et al (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712–716

    PubMed Central  CAS  PubMed  Google Scholar 

  • Minokoshi Y, Haque MS et al (1999) Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes 48:287–291

    CAS  PubMed  Google Scholar 

  • Minokoshi Y, Kim YB et al (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase . Nature 415:339–343

    CAS  PubMed  Google Scholar 

  • Minokoshi Y, Alquier T et al (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574

    CAS  PubMed  Google Scholar 

  • Mootha VK, Lindgren CM et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    CAS  PubMed  Google Scholar 

  • Moule SK, Denton RM (1998) The activation of p38 MAPK by the beta-adrenergic agonist isoproterenol in rat epididymal fat cells. FEBS Lett 439:287–290

    CAS  PubMed  Google Scholar 

  • Moynihan KA, Grimm AA et al (2005) Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2:105–117

    CAS  PubMed  Google Scholar 

  • Muoio DM, Seefeld K et al (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

    PubMed Central  CAS  PubMed  Google Scholar 

  • Murry CE, Jennings RB et al (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    CAS  PubMed  Google Scholar 

  • Musi N, Fujii N et al (2001) AMP-activated protein kinase (AMPK ) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes 50:921–927

    CAS  PubMed  Google Scholar 

  • Narkar VA, Downes M et al (2008) AMPK and PPARdelta agonists are exercise mimetics. Cell 134:405–415

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nathan DM, Buse JB et al (2009) Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52:17–30

    CAS  PubMed  Google Scholar 

  • Nawrocki AR, Rajala MW et al (2006) Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 281:2654–2660

    CAS  PubMed  Google Scholar 

  • Neuschwander-Tetri BA, Caldwell SH (2003) Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37:1202–1219

    PubMed  Google Scholar 

  • Nieto-Vazquez I, Fernandez-Veledo S et al (2008) Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57:3211–3221

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nishino Y, Miura T et al (2004) Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection. Cardiovasc Res 61:610–619

    CAS  PubMed  Google Scholar 

  • Nyblom HK, Sargsyan E et al (2008) AMP-activated protein kinase agonist dose dependently improves function and reduces apoptosis in glucotoxic beta-cells without changing triglyceride levels. J Mol Endocrinol 41:187–194

    CAS  PubMed  Google Scholar 

  • Orci L, Cook WS et al (2004) Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci USA 101:2058–2063

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ouchi N, Kihara S et al (2001) Adipocyte-derived plasma protein, adiponectin , suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103:1057–1063

    CAS  PubMed  Google Scholar 

  • Pacholec M, Bleasdale JE et al (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1 . J Biol Chem 285:8340–8351

    PubMed Central  CAS  PubMed  Google Scholar 

  • Palanivel R, Sweeney G (2005) Regulation of fatty acid uptake and metabolism in L6 skeletal muscle cells by resistin. FEBS Lett 579:5049–5054

    CAS  PubMed  Google Scholar 

  • Pan XR, Li GW et al (1997) Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 20:537–544

    CAS  PubMed  Google Scholar 

  • Park H, Kaushik VK 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 277:32571–32577

    CAS  PubMed  Google Scholar 

  • Petersen KF, Befroy D et al (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance . Science 300:1140–1142

    PubMed Central  CAS  PubMed  Google Scholar 

  • Phillips SA, Ciaraldi TP et al (2003) Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy. Diabetes 52:667–674

    CAS  PubMed  Google Scholar 

  • Picard F, Kurtev M et al (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429:771–776

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pischon T, Girman CJ et al (2004) Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291:1730–1737

    CAS  PubMed  Google Scholar 

  • Pold R, Jensen LS et al (2005) Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 54:928–934

    CAS  PubMed  Google Scholar 

  • Prentki M, Joly E et al (2002) Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 51(Suppl 3):S405–S413

    CAS  PubMed  Google Scholar 

  • Rhodes CJ (2005) Type 2 diabetes-a matter of beta-cell life and death? Science 307:380–384

    CAS  PubMed  Google Scholar 

  • Riboulet-Chavey A, Diraison F et al (2008) Inhibition of AMP-activated protein kinase protects pancreatic beta-cells from cytokine-mediated apoptosis and CD8+ T-cell-induced cytotoxicity. Diabetes 57:415–423

    CAS  PubMed  Google Scholar 

  • Richards SK, Parton LE et al (2005) Over-expression of AMP-activated protein kinase impairs pancreatic {beta}-cell function in vivo. J Endocrinol 187:225–235

    CAS  PubMed  Google Scholar 

  • Roberts CK, Barnard RJ et al (1999) Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am J Physiol 277:E390–E394

    CAS  PubMed  Google Scholar 

  • Rodgers JT, Puigserver P (2007) Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci USA 104:12861–12866

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rossmeisl M, Barbatelli G et al (2002) Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo. Eur J Biochem 269:19–28

    CAS  PubMed  Google Scholar 

  • Rubin LJ, Magliola L et al (2005) Metabolic activation of AMP kinase in vascular smooth muscle. J Appl Physiol 98:296–306

    CAS  PubMed  Google Scholar 

  • Russell RR 3rd, Li J et al (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503

    PubMed Central  CAS  PubMed  Google Scholar 

  • Saha AK, Avilucea PR et al (2004) Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun 314:580–585

    CAS  PubMed  Google Scholar 

  • Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806

    CAS  PubMed  Google Scholar 

  • Sanders MJ, Grondin PO et al (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403:139–148

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sell H, Dietze-Schroeder D et al (2006) Cytokine secretion by human adipocytes is differentially regulated by adiponectin , AICAR , and troglitazone. Biochem Biophys Res Commun 343:700–706

    CAS  PubMed  Google Scholar 

  • Shaw RJ, Lamia KA et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin . Science 310:1642–1646

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shibata R, Ouchi N et al (2004a) Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10:1384–1389

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shibata R, Ouchi N et al (2004b) Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. J Biol Chem 279:28670–28674

    CAS  PubMed  Google Scholar 

  • Shibata R, Sato K et al (2005) Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK - and COX-2-dependent mechanisms. Nat Med 11:1096–1103

    PubMed Central  CAS  PubMed  Google Scholar 

  • Smith AC, Bruce CR et al (2005) AMP kinase activation with AICAR further increases fatty acid oxidation and blunts triacylglycerol hydrolysis in contracting rat soleus muscle. J Physiol 565:547–553

    PubMed Central  CAS  PubMed  Google Scholar 

  • Song XM, Fiedler M et al (2002) 5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45:56–65

    CAS  PubMed  Google Scholar 

  • Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078

    CAS  PubMed  Google Scholar 

  • Steinberg GR, Michell BJ et al (2006) Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 4:465–474

    CAS  PubMed  Google Scholar 

  • Stephens TJ, Chen ZP et al (2002) Progressive increase in human skeletal muscle AMPKalpha2 activity and ACC phosphorylation during exercise. Am J Physiol Endocrinol Metab 282:E688–E694

    CAS  PubMed  Google Scholar 

  • Stoppani J, Hildebrandt AL et al (2002) AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. Am J Physiol Endocrinol Metab 283:E1239–E1248

    CAS  PubMed  Google Scholar 

  • Sullivan JE, Brocklehurst KJ et al (1994) Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR , a cell-permeable activator of AMP-activated protein kinase . FEBS Lett 353:33–36

    CAS  PubMed  Google Scholar 

  • Sun C, Zhang F et al (2007) SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 6:307–319

    CAS  PubMed  Google Scholar 

  • Sun G, Tarasov AI et al (2010) Ablation of AMP-activated protein kinase alpha1 and alpha2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo. Diabetologia 53(5):924–936

    PubMed Central  CAS  PubMed  Google Scholar 

  • Suter M, Riek U et al (2006) Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase . J Biol Chem 281:32207–32216

    CAS  PubMed  Google Scholar 

  • Suzuki A, Okamoto S et al (2007) Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase . Mol Cell Biol 27:4317–4327

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tomas E, Tsao TS et al (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313

    PubMed Central  CAS  PubMed  Google Scholar 

  • Treebak JT, Birk JB et al (2007) AS160 phosphorylation is associated with activation of alpha2beta2gamma1- but not alpha2beta2gamma3-AMPK trimeric complex in skeletal muscle during exercise in humans. Am J Physiol Endocrinol Metab 292:E715–E722

    CAS  PubMed  Google Scholar 

  • Tuomilehto J, Lindstrom J et al (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350

    CAS  PubMed  Google Scholar 

  • U.K. Prospective Diabetes Study Group (1995) U.K. prospective diabetes study 16: Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258

    Google Scholar 

  • Um JH, Park SJ et al (2010) AMP-activated protein kinase -deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59:554–563

    PubMed Central  CAS  PubMed  Google Scholar 

  • Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863–870

    CAS  PubMed  Google Scholar 

  • Van Gaal LF, Mertens IL et al (2006) Mechanisms linking obesity with cardiovascular disease. Nature 444:875–880

    PubMed  Google Scholar 

  • Viana AY, Sakoda H et al (2006) Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression. Diabetes Res Clin Pract 73:135–142

    CAS  PubMed  Google Scholar 

  • Viollet B, Andreelli F et al (2003) Physiological role of AMP-activated protein kinase (AMPK ): insights from knockout mouse models. Biochem Soc Trans 31:216–219

    CAS  PubMed  Google Scholar 

  • Wang X, Zhou L et al (2007) Troglitazone acutely activates AMP-activated protein kinase and inhibits insulin secretion from beta cells. Life Sci 81:160–165

    CAS  PubMed  Google Scholar 

  • Watt MJ, Holmes AG et al (2006) Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 290:E500–E508

    CAS  PubMed  Google Scholar 

  • Weiss EP, Racette SB et al (2006) Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr 84:1033–1042

    PubMed Central  CAS  PubMed  Google Scholar 

  • Willett WC, Dietz WH et al (1999) Guidelines for healthy weight. N Engl J Med 341:427–434

    CAS  PubMed  Google Scholar 

  • Winder WW, Hardie DG (1999) AMP-activated protein kinase , a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 277:E1–E10

    CAS  PubMed  Google Scholar 

  • Winder WW, Holmes BF et al (2000) Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 88:2219–2226

    CAS  PubMed  Google Scholar 

  • Wing RR, Goldstein MG et al (2001) Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity. Diabetes Care 24:117–123

    CAS  PubMed  Google Scholar 

  • Witters LA, Gao G et al (1994) Hepatic 5'-AMP-activated protein kinase : zonal distribution and relationship to acetyl-CoA carboxylase activity in varying nutritional states. Arch Biochem Biophys 308:413–419

    PubMed  Google Scholar 

  • Woods A, Azzout-Marniche D et al (2000) Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol Cell Biol 20:6704–6711

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xu A, Wang Y et al (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112:91–100

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yamauchi T, Kamon J et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946

    CAS  PubMed  Google Scholar 

  • Yamauchi T, Kamon J et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase . Nat Med 8:1288–1295

    CAS  PubMed  Google Scholar 

  • Yamauchi T, Kamon J et al (2003) Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 278:2461–2468

    CAS  PubMed  Google Scholar 

  • Zang M, Xu S et al (2006) Polyphenols stimulate AMP-activated protein kinase , lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180–2191

    CAS  PubMed  Google Scholar 

  • Zarrinpashneh E, Carjaval K et al (2006) Role of the alpha2 isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia. Am J Physiol Heart Circ Physiol 291(6):H2875–H2883

    CAS  PubMed  Google Scholar 

  • Zhang J, Xie Z et al (2008) Identification of nitric oxide as an endogenous activator of the AMP-activated protein kinase in vascular endothelial cells. J Biol Chem 283:27452–27461

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou M, Lin BZ et al (2000) UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase . Am J Physiol Endocrinol Metab 279:E622–E629

    CAS  PubMed  Google Scholar 

  • Zhou G, Myers R et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou L, Wang X et al (2008) Berberine acutely inhibits insulin secretion from beta-cells through 3′, 5′-cyclic adenosine 5′-monophosphate signaling pathway. Endocrinology 149:4510–4518

    CAS  PubMed  Google Scholar 

  • Zong H, Ren JM et al (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99:15983–15987

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zwetsloot KA, Westerkamp LM et al (2008) AMPK regulates basal skeletal muscle capillarization and VEGF expression, but is not necessary for the angiogenic response to exercise. J Physiol 586:6021–6035

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the European Commission integrated project (LSHM-CT-2004-005272/exgenesis), Agence Nationale de la Recherche (ANR-06-PHYSIO-026), Association Française contre les Myopathies (AFM), Association pour l’Etude des Diabètes et des Maladies Métaboliques (ALFEDIAM), and Institut Benjamin Delessert.

Author information

Authors and Affiliations

  1. Inserm, U1016, Institut Cochin, Paris, France

    Benoit Viollet & Fabrizio Andreelli

  2. Cnrs, UMR8104, Paris, France

    Benoit Viollet & Fabrizio Andreelli

  3. Univ Paris Descartes, Paris, France

    Benoit Viollet & Fabrizio Andreelli

  4. Department of Diabetology, Pitié-Salpêtrière Hospital (AP-HP), Univ Pierre et Marie Curie-Paris 6, Paris, France

    Fabrizio Andreelli

Authors
  1. Benoit Viollet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabrizio Andreelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benoit Viollet .

Editor information

Editors and Affiliations

  1. Fakultät Lebenswissenschaften Molekulare Pharmakologie und Toxikologie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany

    Mathias Schwanstecher

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Viollet, B., Andreelli, F. (2011). AMP-Activated Protein Kinase and Metabolic Control. In: Schwanstecher, M. (eds) Diabetes - Perspectives in Drug Therapy. Handbook of Experimental Pharmacology, vol 203. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17214-4_13

Download citation

Publish with us

Policies and ethics

Search

Navigation