• Users Online: 59
  • Print this page
  • Email this page

 Table of Contents  
Year : 2022  |  Volume : 1  |  Issue : 1  |  Page : 18-26

Regulation and role of amp-activated protein kinase at the cellular level and relevance to diabetes mellitus

Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Submission19-Oct-2021
Date of Decision17-Nov-2021
Date of Acceptance17-Nov-2021
Date of Web Publication07-Jan-2022

Correspondence Address:
Paresh P Kulkarni
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cdrp.cdrp_5_21

Rights and Permissions

Adenosine Mono phosphate -activated protein kinase (AMPK) is a metabolic master switch that senses the cellular AMP levels. However, it is now also regarded as a nutrient-sensing enzyme due to its ability to detect glucose deprivation inside the cell. Under conditions of energy deprivation, AMPK is activated, which in turn switches on all the energy-producing metabolic pathways, while switching off energy-consuming metabolic pathways and cellular processes. There is a growing interest in AMPK due to its role in a wide array of pathological processes including diabetes mellitus. It is the therapeutic target of one of the most commonly prescribed classes of antidiabetic drugs, namely the biguanides such as metformin. The current article presents a review of AMPK structure, triggers, and mechanisms of its activation as well as its role in cell metabolism, mitochondrial homeostasis, autophagy, and cell proliferation. It also briefly addresses the relevance of AMPK to pathogenesis and management of diabetes mellitus.

Keywords: AMP-activated protein kinase, autophagy, carbohydrate metabolism, diabetes mellitus, lipid metabolism, mitochondrial homeostasis

How to cite this article:
Kulkarni PP. Regulation and role of amp-activated protein kinase at the cellular level and relevance to diabetes mellitus. Chron Diabetes Res Pract 2022;1:18-26

How to cite this URL:
Kulkarni PP. Regulation and role of amp-activated protein kinase at the cellular level and relevance to diabetes mellitus. Chron Diabetes Res Pract [serial online] 2022 [cited 2023 Mar 29];1:18-26. Available from: https://cdrpj.org//text.asp?2022/1/1/18/335257

  Introduction Top

In order to survive and function, cells should be able to sense deprivation of energy as well as nutrient substrates. Cells need to then respond by adjusting their metabolism to conserve their energy resources and restore cellular energy balance. They may do so by decreasing energy consumption, increasing nutrient uptake and catabolism, mobilizing alternative energy-generating pathways, and recycling existing macromolecules into nutrients.[1] Evolution has led to the emergence of an ultrasensitive energy-sensing mechanism in the form of AMP-activated protein kinase (AMPK) that allows eukaryotic cells to modulate cellular processes according to energy status.[1]

At the cellular level, energy stress in the form of decreased energy supply relative to demand is reflected as decrease in Adenosine Diphosphate (ADP) Adenosine Triphosphate (ATP) and ATP/AMP ratios.[2] AMPK is activated by AMP and to a lesser extent ADP, when cellular ATP levels are low.[3] Upon activation, it acts a metabolic master switch that turns off energy-consuming anabolic pathways while turning on energy-producing catabolic pathways. AMPK influences several cellular processes including lipid and carbohydrate metabolism, mitochondrial homeostasis, autophagy, and cell growth.[1],[2]

There has been a recent surge in interest for studying AMPK due to four reasons. First, AMPK is activated by calorie restriction[4] and exercise[5] that are linked to increased life span as well as health span. Second, AMPK has emerged as an attractive therapeutic target in a myriad of pathologies such as diabetes mellitus,[6] obesity,[7] nonalcoholic fatty liver disease,[8] cardiovascular disease,[9] cancer[10], neurodegenerative diseases,[11] and thrombosis[12] [Figure 1].[2] Third, a plethora of small-molecule pharmacological modulators of AMPK activity have become available.[2] Finally, understanding the regulation and roles of AMPK, a metabolic master regulator, is of particular importance for management of metabolic disorders such as diabetes mellitus.
Figure 1: AMP-activated protein kinase influences pathogenesis of a wide array of disorders

Click here to view

  Regulation of AMP-Activated Protein Kinase Top

Structure of AMP-activated protein kinase

AMPK is a heterotrimeric complex that is composed of one catalytic subunit and two regulatory subunits [Figure 2]. α-subunit is the catalytic subunit encoded by PRKAA gene, and has two isoforms. The regulatory subunits are β- and γ-subunits encoded by PRKAB and PRKAG genes, respectively. β-subunit has two isoforms, while γ-subunit has three. All combinations of subunit isoforms are possible in forming the heterotrimer, thus generating 12 different AMPK complexes.[1],[2]
Figure 2: Scheme depicting structure of AMP-activated protein kinase subunits

Click here to view

α-subunit has a typical serine/threonine kinase domain at the amino-terminal region, which is responsible for catalytic activity of AMPK. An activation loop or T-loop is embedded within the kinase domain, which carries a threonine 172 residue whose phosphorylation is pivotal to the mechanism of AMPK activation.[13],[14] To the carboxy-terminal side of kinase domain is the auto-inhibitory domain (AID), which has a sequence of amino acids that reduces the activity of kinase domain by several folds.[15] α-regulatory subunit-interacting motif 2, found adjacent to AID toward carboxy-terminus, is a short sequence of amino acids which is critical to AMP/ADP-dependent activation of AMPK.[16]

β-subunit carries the carbohydrate-binding domain (CBD) that allows AMPK to associate with glycogen and the enzymes involved in glycogen metabolism.[17] Furthermore, CBD is involved in forming the binding site for small-molecule AMPK activators.[2] The scaffold for assembly of αβγ complex is provided by the carboxy-terminal end of β-subunit.[18] The amino-terminal end of β-subunit is constitutively myristoylated to facilitate adenine nucleotide-dependent phosphorylation of Thr172.[19]

γ-subunit contains four cystathionine-β-synthase domains (CBS1, CBS2, CBS3, and CBS4) toward the carboxy-terminus.[20] CBS4 is permanently occupied by an AMP molecule[18] while CBS2 does not bind AMP/ADP/ATP.[21] CBS1 and CBS3 that reversibly bind to AMP/ADP/ATP are responsible for adenylate charge sensing by AMPK.[18] γ1 isoform lacks the amino-terminal extensions that are found in γ2 and γ3 isoforms, which may lead to differences between these isoforms in AMPK activation by AMP/ADP and small-molecule activators.[22]

Activation of AMP-activated protein kinase

AMPK activity is tightly regulated by several hormonal and metabolic cues.[2] There are three principal signals, which can independently activate AMPK, namely cellular adenylate charge,[3] rise in intracellular calcium,[23] and glucose starvation [Figure 3].[24] Although AMPK responds to both AMP and ADP, it is likely that AMP is the major mediator of AMPK activation in vivo.[25] There are three possible mechanisms by which AMP activates AMPK.[1] First, it increases the phosphorylation of Thr172 by upstream kinase, namely liver kinase B1 (LKB1).[26],[27] Second, it protects Thr172 from dephosphorylation by phosphatases.[28] Third, it allosterically activates AMPK that is already phosphorylated at Thr172.[13],[25] ADP does not have a direct allosteric effect on AMPK, and can activate AMPK by the former two mechanisms.[3]
Figure 3: Triggers and mechanisms of AMP-activated protein kinase activation

Click here to view

A rise in intracellular calcium in response to hormones, growth factors, or agonists can also activate AMPK through phosphorylation of Thr172 by calcium/calmodulin-dependent kinase kinase 2 (CAMKK2).[23],[29],[30],[31],[32] CAMKK2 also activates AMPK in response to amino acid deprivation[33] and hypoxia.[34] Low glucose levels lead to decreased levels of the glycolytic intermediate fructose 1,6-bisphosphate (FBP) and consequent decrease in FBP binding to aldolase. This promotes AMPK phosphorylation at Thr172 by LKB1 independent of AMP through their binding to vacuolar ATPase and axin on the lysosome.[24]

  Plethora of AMP-Activated Protein Kinase Functions inside the Cell Top

Regulation of carbohydrate metabolism by AMP-activated protein kinase

AMPK regulates carbohydrate metabolism by influencing glucose uptake, glycogen metabolism, glycolysis, and gluconeogenesis [Figure 4]. AMPK stimulates glucose uptake by skeletal muscle through Glucose transporter type 4 (GLUT4) translocation to plasma membrane by two mechanisms. First, it phosphorylates and inhibits TBC1 domain family member 1 (TBC1D1), which otherwise localizes GLUT4 to Golgi apparatus.[35] Second, it activates extracellular signal-regulated kinase (ERK) through phosphorylation of 1-phosphatidylinositol 3-phosphate 5-kinase (PIKfyve)[36] and phospholipase D1.[37] ERK in turn promotes GLUT4 translocation to plasma membrane. In addition, AMPK increases GLUT4 gene expression by phosphorylating histone deacetylase (HDAC).[38] Unlike myocytes, most other cells in our body take up glucose through activation of plasma membrane GLUT1[39] and enhanced GLUT1 expression[40] by AMPK. It also increases GLUT1 translocation to plasma membrane and gene expression through phosphorylation and degradation of thioredoxin-interacting protein.[41]
Figure 4: Role of AMP-activated protein kinase in regulating carbohydrate metabolism

Click here to view

AMPK phosphorylates and activates 6-phosphofructo-2-kinase, which generates fructose 2,6-bisphosphate the most potent activator of the rate-limiting enzyme of glycolysis, namely 6-phosphofructo-1-kinase.[42] AMPK promotes glycolysis by upregulating gene expression of hexokinase[43] and liver pyruvate kinase.[44] Glycogen synthase undergoes inhibitory phosphorylation by AMPK, thus preventing glycogenesis.[45] Glutamine fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of hexosamine biosynthesis, is phosphorylated and inhibited by AMPK.[46] Thus, inhibition of glycogen synthase and GFAT1 increases flux of glucose-6-phosphate through glycolysis.

AMPK inhibits gluconeogenesis through multiple mechanisms. First, it phosphorylates and activates phosphodiesterase 4B, which prevents cAMP elevation in response to glucagon.[47] Second, it facilitates inhibition of gluconeogenesis by insulin through reduction in lipid-induced insulin resistance.[48] Third, it represses expression of gluconeogenesis enzymes through phosphorylation of CREB- regulated transcription co-activator 2[49] and Class IIA histone deacetylases.[38]

Regulation of lipid metabolism by AMP-activated protein kinase

AMPK independently regulates fatty acid, triacylglycerol, and cholesterol metabolism [Figure 5]. AMPK downregulates fatty acid and cholesterol synthesis through inhibitory phosphorylation of acetyl-CoA carboxylase (ACC)[48] and HMG-CoA reductase (HMGR),[50],[51] respectively. It also influences these metabolic pathways through inhibitory phosphorylation of transcription factors sterol response element-binding protein 1 (SREBP1) and SREBP2. SREBP1 otherwise increases gene expression of ATP-citrate lyase, ACC, and fatty acid synthase, while SREBP2 upregulates expression of HMGR and LDL receptor.[52] In addition, AMPK can indirectly inhibit SREBPs through p53, sirtuins, and forkhead box protein (FOXO).[53],[54]
Figure 5: Role of AMP-activated protein kinase in regulating lipid metabolism

Click here to view

AMPK stimulates mobilization and breakdown of lipids to generate ATP.[1] It increases lipolysis by activating adipose triglyceride lipase and hormone-sensitive lipase[55],[56] as well as by inactivating glycerol-3-phosphate acyltransferase.[57] It enhances uptake of fatty acids into the cells through CD36 by increasing its translocation to plasma membrane.[58] The rate-limiting step of β-oxidation of fatty acids is the entry of fatty acyl-CoA into the mitochondria catalyzed by carnitine palmitoyltransferase 1 (CPT1). Malonyl-CoA generated from acetyl-CoA by the action of ACC is an allosteric inhibitor of CPT1. AMPK thus stimulates β-oxidation of fatty acids by relieving CPT1 from inhibition by malonyl-CoA through inhibitory phosphorylation of ACC.[48] It can also increase fatty acid oxidation independent of ACC regulation under energy-demanding conditions.[59],[60]

Regulation of mitochondrial homeostasis and autophagy by AMP-activated protein kinase

AMPK regulates mitochondrial homeostasis by promoting both generation of healthy mitochondria and removal of dysfunctional mitochondria [Figure 6]. AMPK increases mitochondrial content through phosphorylation and activation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α),[61] which is the master regulator of mitochondrial biogenesis.[62] AMPK also promotes gene expression of PGC1α through activation of transcription factor EB.[63] Further, AMPK may also upregulate PGC1α indirectly through p53, SIRT1, and HDAC.[64] In parallel with increase in mitochondrial biogenesis, there needs to be removal of damaged mitochondria to improve mitochondrial function.[65] AMPK phosphorylates mitochondrial fission factor and initiates mitochondrial fission[66] before the dysfunctional mitochondria can be degraded by mitophagy, which is a selective form of autophagy. It also triggers mitochondrial fission through dynamin-related protein 1 (DRP1) by phosphorylation of A kinase anchor protein 1 (AKAP1), which in turn promotes protein kinase A-dependent activation of DRP1.[67]
Figure 6: Role of AMP-activated protein kinase in regulating mitochondrial homeostasis

Click here to view

Mitophagy or autophagy is promoted by AMPK through various mechanisms, which could be either ULK-1 dependent [Figure 7] or independent [Figure 8]. First, it phosphorylates and activates unc-51-like autophagy-activating kinase 1 (ULK1), which is vital to initiation of autophagosome formation.[68],[69] Second, it aids formation of pro-autophagy Class III PI3kinase (or Vps34) complex by phosphorylating autophagy-related protein 9 (ATG9) and beclin 1.[70] Third, it relieves ULK1 from inhibitory phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) through phosphorylation of tuberous sclerosis complex 2 (TSC2) (a negative regulator of mTOR activity)[71] and Raptor (a subunit of mTORC1).[72] Fourth, it fosters acetylation and activation of nuclear transcription factors that initiate lysosome biogenesis through activatory phosphorylation of acetyl-CoA synthetase.[73] Finally, it increases gene expression of autophagy-related proteins light chain 3 (LC3), beclin 1, VpS34, and BCL2 interacting protein 3 (BNIP3) by phosphorylation and activation of FOXO3 transcription factor.[74],[75]
Figure 7: ULK-1-dependent regulation of autophagy by AMP-activated protein kinase

Click here to view
Figure 8: ULK-1-independent regulation of autophagy by AMP-activated protein kinase

Click here to view

Regulation of protein synthesis and cell growth by AMP-activated protein kinase

AMPK inhibits protein translation and cell growth, which consume bulk of ATP [Figure 9]. It negatively regulates mTORC1 as described in the previous paragraph [Figure 7]. It also phosphorylates and activates eukaryotic elongation factor 2 kinase, which in turn switches off protein synthesis by phosphorylating eukaryotic elongation factor 2.[76] Further, AMPK is also known to influence various pathways related to cell growth including Hedgehog,[77] Hippo,[78] Janus kinase (JAK)- signal transducer and activator of transcription (STAT),[79] and p53[80] signaling pathways.
Figure 9: Role of AMP-activated protein kinase in regulating protein synthesis

Click here to view

  Role of AMP-Activated Protein Kinase in Pathogenesis of Diabetes Mellitus Top

The cardinal features of diabetes mellitus are defective insulin secretion and insulin resistance. The major organs exhibiting insulin resistance are skeletal muscle, liver, and adipose tissue.[81] Evidence from animal models and human participants points to a role of deranged AMPK activity in the pathogenesis of insulin resistance and diabetes.[82] Further, physiological or pharmacological activation of AMPK improves insulin sensitivity as well as favorably influences glucose homeostasis in an insulin-independent fashion.[6],[81]

AMP-activated protein kinase activity in animal models of insulin resistance and diabetes

Genetically modified animals with obesity including leptin-deficient mice (ob/ob) and leptin receptor-deficient rats (fa/fa) exhibit impaired AMPK activity. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMPK activator, recovered insulin sensitivity and glucose tolerance in these rodents.[83],[84],[85],[86] A rodent model of early-onset diabetes named Zucker diabetic fatty (ZDF) rats, which have a genetic leptin receptor deficiency and a mutation in the promoter region of insulin gene, also show decreased AMPK activity.[87] AICAR and exercise were found to entirely preclude the onset of diabetes in ZDF rats.[88] Other AMPK activators including antidiabetic drugs had a similar effect in fa/fa rats.[89],[90] As a corollary, genetically induced deficiency of AMPK activity in mice fed with high-fat diet worsens insulin resistance.[91],[92] The beneficial effect of polyphenol on insulin sensitivity in mice on high-fat diet was abolished upon knocking out AMPK α2 gene.[93]

AMP-activated protein kinase activity in humans with insulin resistance

Patients of Cushing's syndrome with an adrenal adenoma that secretes glucocorticoids characteristically exhibit insulin resistance and an increased risk of developing diabetes.[82] These patients show decreased AMPK activity in adipose tissue, which could underlie the associated metabolic alterations.[94] Roughly three-quarters of morbidly obese individuals undergoing bariatric surgery were found to be insulin resistant with an associated decrease in AMPK activity, inflammatory cell infiltration, altered gene expression of key inflammatory mediators, and metabolic enzymes in adipose tissue.[95],[96],[97] The remaining quarter of individuals were insulin sensitive, and had normal adipocyte AMPK activity.[98],[99] Patients of diabetes mellitus or obesity also exhibit decreased AMPK activity in skeletal muscle[100] and an impairment in exercise-induced AMPK activation.[101]

Cross-talk between AMP-activated protein kinase and inflammation underlying insulin resistance

Inflammation in adipose tissue precedes the onset of insulin resistance in diabetes. There is a two-way relationship between AMPK and inflammation. On the one hand, AMPK checks inflammation, while on the other hand, inflammation diminishes AMPK activity.[82] Treatment of macrophages with anti-inflammatory IL-10 activates AMPK, while the pro-inflammatory lipopolysaccharide (LPS) inactivates AMPK.[102] Inhibition of AMPK by genetic manipulation exacerbates LPS-induced inflammation.[102] AMPK inactivation in macrophages induces insulin resistance in co-cultured adipocytes.[103] Activation of AMPK diminishes expression of inflammatory genes in macrophages and adipocytes.[104] Expression of constitutively active AMPK in macrophages abolishes LPS/palmitate-induced pro-inflammatory Nuclear factor kappa B (NF-κB) signaling.[103] AMPK activation abolishes switch in adipocyte macrophages to M1 phenotype by autophagy-mediated improvement in mitochondrial function.[82],[105]

  Relevance of AMP-Activated Protein Kinase to Management of Diabetes Mellitus Top

Management of diabetes mellitus involves use of lifestyle interventions as well as antidiabetic drugs. Lifestyle interventions such as calorie restriction and exercise as well as antidiabetic drugs such as biguanides, thiazolidinediones, and glucagon-like peptide 1 (GLP-1) are known to induce AMPK activation.[106] The therapeutic effects of the aforementioned approaches to manage diabetes are at least in part mediated by AMPK.

Calorie restriction and exercise

Energy stress induced by calorie restriction or exercise is known to increase AMP/ATP ratio and thereby activate AMPK.[107] In agreement, AMPK is activated by contraction in the skeletal muscle of both rodents[108] and humans.[109] AMPK is a crucial mediator of the beneficial effects of exercise on glucose homeostasis.[110] Pharmacological activation of AMPK mimics the metabolic effects of exercise.[107] Mice with genetic deficiency of AMPK in skeletal muscle have reduced exercise tolerance as well as impaired contraction-stimulated glucose uptake and mitochondrial biogenesis.[111],[112]


It is the only biguanide currently employed in the management of diabetes[113] and the first-line oral antidiabetic drug.[114] Metformin is known to act by inhibiting complex I of electron transport chain (ETC) in the mitochondria.[115] It increases intracellular AMP/ATP ratio and thereby activates AMPK indirectly, which in turn mediates metformin's insulin-sensitizing action.[116] However, metformin treatment was able to exert hypoglycemic effect in mice with genetic deficiency of AMPK or LKB1.[117] It has been shown to antagonize glucagon signaling through cyclic AMP in an AMPK-independent manner.[118] In contrast, mutant mice on high-fat diet, in which ACC1/ACC2 is rendered resistant to inhibitory phosphorylation by AMPK, exhibit compromised insulin-sensitizing effect of metformin.[48] These results suggest that at least some of the therapeutic effects of metformin in diabetic patients are likely mediated by AMPK.


They are a class of insulin-sensitizing drugs whose mechanism of action is activation of peroxisome proliferator-activated receptor-γ. However, they have been shown to wield some of their antidiabetic effects through activation of AMPK.[119] They are known to increase AMPK activity in skeletal muscle, adipose tissue, and liver[120],[121] by a mechanism similar to metformin that involves inhibition of complex I of ETC.[119]

Glucagon-like peptide 1 receptor agonists

These drugs mimic GLP-1, which is secreted from intestinal cells in response to food intake. GLP-1 potentiates glucose-induced insulin release and inhibits glucagon secretion from pancreas.[122] However, GLP-1 mimetics including exenatide and liraglutide can also activate AMPK signaling in liver, through increased transcription, translation, and phosphorylation of AMPK. Exenatide, in particular, has been known to reduce intrahepatocyte lipid synthesis and accumulation as well as hepatic inflammation in mice on high-fat diet, effects which could be mediated by AMPK as discussed earlier.[123],[124]

  Conclusion Top

AMPK plays a critical role in cell's ability to sense and adapt to energy deprivation. It is a metabolic master switch activated by energy stress, which regulates a myriad of cellular processes, particularly metabolism of carbohydrates and lipids. Hence, understanding the regulation and function of AMPK is fundamental for comprehending the pathogenesis of diseases associated with deranged cell metabolism. A plethora of small molecules that directly or indirectly activate AMPK have become available, thus opening up exciting avenues for developing novel drugs for use in the management of a wide array of disorders, particularly diabetes mellitus.

Financial support and sponsorship

This study was financially supported by Banaras Hindu University, Varanasi, India.

Conflicts of interest

There are no conflicts of interest.

  References Top

Herzig S, Shaw RJ. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 2018;19:121-35.  Back to cited text no. 1
Steinberg GR, Carling D. AMP-activated protein kinase: The current landscape for drug development. Nat Rev Drug Discov 2019;18:527-51.  Back to cited text no. 2
Oakhill JS, Steel R, Chen Z-P, Scott JW, Ling N, Tam S, et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 2011;332:1433-5.  Back to cited text no. 3
Witters LA, Gao G, Kemp BE, Quistorff B. Hepatic 5'-AMP-activated protein kinase: Zonal distribution and relationship to acetyl-coa carboxylase activity in varying nutritional states. Arch Biochem Biophys 1994;308:413-9.  Back to cited text no. 4
Winder WW, Hardie DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol 1996;270 2 Pt 1:E299-304.  Back to cited text no. 5
Musi N. AMP-activated protein kinase and Type 2 diabetes. Curr Med Chem 2006;13:583-9.  Back to cited text no. 6
Kola B, Grossman A, Korbonits M. The role of AMP-activated protein kinase in obesity. In: Frontiers of Hormone Research. Basel, Switzerland: Karger Publishers; 2008. p. 198-211.  Back to cited text no. 7
von Loeffelholz C, Coldewey SM, Birkenfeld AL. A narrative review on the role of ampk on de novo lipogenesis in non-alcoholic fatty liver disease: Evidence from human studies. Cells 2021;10:1822.  Back to cited text no. 8
Salt IP, Hardie DG. AMP-activated protein kinase. Circ Res 2017;120:1825-41.  Back to cited text no. 9
Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett 2015;356 (2 Part A):165-70.  Back to cited text no. 10
Wang X, Zimmermann HR, Ma T. Therapeutic potential of AMP-activated protein kinase in Alzheimer's disease. J Alzheimers Dis 2019;68:33-8.  Back to cited text no. 11
Kulkarni PP, Sonkar VK, Gautam D, Dash D. AMPK inhibition protects against arterial thrombosis while sparing hemostasis through differential modulation of platelet responses. Thromb Res 2020;196:175-85.  Back to cited text no. 12
Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D. Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 2006;281:32207-16.  Back to cited text no. 13
Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 2007;403:139-48.  Back to cited text no. 14
Pang T, Xiong B, Li JY, Qiu BY, Jin GZ, Shen JK, et al. Conserved α-helix acts as autoinhibitory sequence in AMP-activated protein kinase α subunits. J Biol Chem 2007;282:495-506.  Back to cited text no. 15
Xin FJ, Wang J, Zhao RQ, Wang ZX, Wu JW. Coordinated regulation of AMPK activity by multiple elements in the α-subunit. Cell Res 2013;23:1237-40.  Back to cited text no. 16
Machovič M, Janeček Š. The evolution of putative starch-binding domains. FEBS Lett 2006;580:6349-56.  Back to cited text no. 17
Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 2007;449:496-500.  Back to cited text no. 18
Oakhill JS, Chen ZP, Scott JW, Steel R, Castelli LA, Ling N, et al. β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci 2010;107:19237-41.  Back to cited text no. 19
Cheung PC, Salt IP, Davies SP, Hardie DG, Carling D. Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem J 2000;346 Pt 3:659-69.  Back to cited text no. 20
Kemp BE, Oakhill JS, Scott JW. AMPK structure and regulation from three angles. Structure 2007;15:1161-3.  Back to cited text no. 21
Willows R, Navaratnam N, Lima A, Read J, Carling D. Effect of different γ-subunit isoforms on the regulation of AMPK. Biochem J 2017;474:1741-54.  Back to cited text no. 22
Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2005;2:21-33.  Back to cited text no. 23
Zhang CS, Hawley SA, Zong Y, Li M, Wang Z, Gray A, et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 2017;548:112-6.  Back to cited text no. 24
Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 2013;18:556-66.  Back to cited text no. 25
Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003;2:28.  Back to cited text no. 26
Hawley SA, Selbert MA, Goldstein EG, Edelman AM, Carling D, Hardie DG. 5'-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J Biol Chem 1995;270:27186-91.  Back to cited text no. 27
Stephen D, Nicholas H, Patricica C, Graham H. 5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2Cα and native bovine protein phosphatase-2Ac. FEBS Lett 1995;377:421-5.  Back to cited text no. 28
Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab 2008;7:377-88.  Back to cited text no. 29
Yamauchi M, Kambe F, Cao X, Lu X, Kozaki Y, Oiso Y, et al. Thyroid hormone activates adenosine 5'-monophosphate-activated protein kinase via intracellular calcium mobilization and activation of calcium/calmodulin-dependent protein kinase kinase-beta. Mol Endocrinol (Baltimore, Md) 2008;22:893-903.  Back to cited text no. 30
Stahmann N, Woods A, Carling D, Heller R. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol Cell Biol 2006;26:5933-45.  Back to cited text no. 31
Tamás P, Hawley SA, Clarke RG, Mustard KJ, Green K, Hardie DG, et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 2006;203:1665-70.  Back to cited text no. 32
Ghislat G, Patron M, Rizzuto R, Knecht E. Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-β (CaMKK-β). J Biol Chem 2012;287:38625-36.  Back to cited text no. 33
Mungai PT, Waypa GB, Jairaman A, Prakriya M, Dokic D, Ball MK, et al. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 2011;31:3531-45.  Back to cited text no. 34
Taylor EB, An D, Kramer HF, Yu H, Fujii NL, Roeckl KS, et al. Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J Biol Chem 2008;283:9787-96.  Back to cited text no. 35
Liu Y, Lai YC, Hill EV, Tyteca D, Carpentier S, Ingvaldsen A, et al. Phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) is an AMPK target participating in contraction-stimulated glucose uptake in skeletal muscle. Biochem J 2013;455:195-206.  Back to cited text no. 36
Kim JH, Park JM, Yea K, Kim HW, Suh PG, Ryu SH. Phospholipase D1 mediates AMP-activated protein kinase signaling for glucose uptake. PLoS One 2010;5:e9600.  Back to cited text no. 37
Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez JG, et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 2011;145:607-21.  Back to cited text no. 38
Abbud W, Habinowski S, Zhang J-Z, Kendrew J, Elkairi FS, Kemp BE, et al. Stimulation of AMP-activated protein kinase (AMPK) is associated with enhancement of glut1-mediated glucose transport. Arch Biochem Biophys 2000;380:347-52.  Back to cited text no. 39
Fryer LG, Foufelle F, Barnes K, Baldwin SA, Woods A, Carling D. Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells. Biochem J 2002;363 Pt 1:167-74.  Back to cited text no. 40
Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell 2013;49:1167-75.  Back to cited text no. 41
Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 2000;10:1247-55.  Back to cited text no. 42
Stoppani J, Hildebrandt AL, Sakamoto K, Cameron-Smith D, Goodyear LJ, Neufer PD. AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. Am J Physiol Endocrinol Metab 2002;283:E1239-48.  Back to cited text no. 43
Leclerc I, Lenzner C, Gourdon L, Vaulont S, Kahn A, Viollet B. Hepatocyte nuclear factor-4α involved in Type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. Diabetes 2001;50:1515-21.  Back to cited text no. 44
Carling D, Grahame Hardie D. The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase. Biochim Biophys Acta 1989;1012:81-6.  Back to cited text no. 45
Zibrova D, Vandermoere F, Göransson O, Peggie M, Mariño K v, Knierim A, et al. GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. Biochem J 2017;474:983-1001.  Back to cited text no. 46
Johanns M, Lai YC, Hsu M-F, Jacobs R, Vertommen D, van Sande J, et al. AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nat Commun 2016;7:10856.  Back to cited text no. 47
Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013;19:1649-54.  Back to cited text no. 48
Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 2005;437:1109-14.  Back to cited text no. 49
Loh K, Tam S, Murray-Segal L, Huynh K, Meikle PJ, Scott JW, et al. Inhibition of adenosine monophosphate-activated protein kinase-3-hydroxy-3-methylglutaryl coenzyme a reductase signaling leads to hypercholesterolemia and promotes hepatic 7steatosis and insulin resistance. Hepatol Commun 2018;3:84-98.  Back to cited text no. 50
Carling D, Zammit VA, Hardie DG. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 1987;223:217-22.  Back to cited text no. 51
Ye J, DeBose-Boyd RA. Regulation of cholesterol and fatty acid synthesis. Cold Spring Harb Perspect Biol 2011;3:a004754.  Back to cited text no. 52
Lee CW, Wong LL, Tse EY, Liu HF, Leong VY, Lee JM, et al. AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Res 2012;72:4394-404.  Back to cited text no. 53
Haeusler RA, Hartil K, Vaitheesvaran B, Arrieta-Cruz I, Knight CM, Cook JR, et al. Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat Commun 2014;5:5190.  Back to cited text no. 54
Ahmadian M, Abbott MJ, Tang T, Hudak CSS, Kim Y, Bruss M, et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab 2011;13:739-48.  Back to cited text no. 55
Kim SJ, Tang T, Abbott M, Viscarra JA, Wang Y, Sul HS. AMPK phosphorylates desnutrin/ATGL and hormone-sensitive lipase to regulate lipolysis and fatty acid oxidation within adipose tissue. Mol Cell Biol 2016;36:1961-76.  Back to cited text no. 56
Muoio DM, Seefeld K, Witters LA, Coleman RA. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: Evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem J 1999;338 Pt 3:783-91.  Back to cited text no. 57
Momken I, Chabowski A, Dirkx E, Nabben M, Jain SS, McFarlan JT, et al. A new leptin-mediated mechanism for stimulating fatty acid oxidation: A pivotal role for sarcolemmal FAT/CD36. Biochem J 2016;474:149-62.  Back to cited text no. 58
Zordoky BN, Nagendran J, Pulinilkunnil T, Kienesberger PC, Masson G, Waller TJ, et al. AMPK-dependent inhibitory phosphorylation of ACC is not essential for maintaining myocardial fatty acid oxidation. Circ Res 2014;115:518-24.  Back to cited text no. 59
O'Neill HM, Lally JS, Galic S, Pulinilkunnil T, Ford RJ, Dyck JR, et al. Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. Physiol Rep 2015;3:e12444.  Back to cited text no. 60
Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 2007;104:12017-22.  Back to cited text no. 61
Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 2002;418:797-801.  Back to cited text no. 62
Settembre C, de Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol 2013;15:647-58.  Back to cited text no. 63
O'Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: Implications for obesity. Mol Cell Endocrinol 2013;366:135-51.  Back to cited text no. 64
Garcia D, Shaw RJ. AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 2017;66:789-800.  Back to cited text no. 65
Toyama EQ, Herzig S, Courchet J, Lewis TL Jr., Losón OC, Hellberg K, et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 2016;351:275-81.  Back to cited text no. 66
Hoffman NJ, Parker BL, Chaudhuri R, Fisher-Wellman KH, Kleinert M, Humphrey SJ, et al. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab 2015;22:922-35.  Back to cited text no. 67
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132-41.  Back to cited text no. 68
Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011;331:456-61.  Back to cited text no. 69
Zhang D, Wang W, Sun X, Xu D, Wang C, Zhang Q, et al. AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy 2016;12:1447-59.  Back to cited text no. 70
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-90.  Back to cited text no. 71
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-26.  Back to cited text no. 72
Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee JH, et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol Cell 2017;66:684-97.e9.  Back to cited text no. 73
Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, del Piccolo P, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007;6:458-71.  Back to cited text no. 74
Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 2007;282:30107-19.  Back to cited text no. 75
Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M, et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 2013;153:1064-79.  Back to cited text no. 76
Li YH, Luo J, Mosley YY, Hedrick VE, Paul LN, Chang J, et al. AMP-activated protein kinase directly phosphorylates and destabilizes hedgehog pathway transcription factor GLI1 in medulloblastoma. Cell Rep 2015;12:599-609.  Back to cited text no. 77
Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S, et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol 2015;17:500-10.  Back to cited text no. 78
Rutherford C, Speirs C, Williams JJL, Ewart MA, Mancini SJ, Hawley SA, et al. Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Sci Signal 2016;9:ra109.  Back to cited text no. 79
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005;18:283-93.  Back to cited text no. 80
Zhang BB, Zhou G, Li C. AMPK: An emerging drug target for diabetes and the metabolic syndrome. Cell Metab 2009;9:407-16.  Back to cited text no. 81
Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Investig 2013;123:2764-72.  Back to cited text no. 82
Bergeron R, Russell RR, Young LH, Ren JM, Marcucci M, Lee A, et al. Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol Endocrinol Metab 1999;276:E938-44.  Back to cited text no. 83
Song XM, Fiedler M, Galuska D, Ryder JW, Fernström M, Chibalin AV, et al. 5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 2002;45:56-65.  Back to cited text no. 84
Halseth AE, Ensor NJ, White TA, Ross SA, Gulve EA. Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. Biochem Biophys Res Commun 2002;294:798-805.  Back to cited text no. 85
Buhl ES, Jessen N, Pold R, Ledet T, Flyvbjerg A, Pedersen SB, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 2002;51:2199-206.  Back to cited text no. 86
Yu X, McCorkle S, Wang M, Lee Y, Li J, Saha AK, et al. Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: Prevention of diabetes and ectopic lipid deposition. Diabetologia 2004;47:2012-21.  Back to cited text no. 87
Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, et al. Long-Term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 2005;54:928.  Back to cited text no. 88
de Souza CJ, Yu JH, Robinson DD, Ulrich RG, Meglasson MD. Insulin secretory defect in zucker fa/fa rats is improved by ameliorating insulin resistance. Diabetes 1995;44:984-91.  Back to cited text no. 89
Matthaei S, Reibold JP, Hamann A, Benecke H, Häring HU, Greten H, et al. In vivo metformin treatment ameliorates insulin resistance: Evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes. Endocrinology 1993;133:304-11.  Back to cited text no. 90
Biplab D, Sun JJ, Yo S, Xiaona L, Su-Ryun J, Kazuhiko H, et al. The AMPK β2 subunit is required for energy homeostasis during metabolic stress. Mol Cell Biol 2012;32:2837-48.  Back to cited text no. 91
Fujii N, Ho RC, Manabe Y, Jessen N, Toyoda T, Holland WL, et al. Ablation of AMP-activated protein kinase α2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes 2008;57:2958-66.  Back to cited text no. 92
Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010;59:554-63.  Back to cited text no. 93
Kola B, Christ-Crain M, Lolli F, Arnaldi G, Giacchetti G, Boscaro M, et al. Changes in adenosine 5'-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome. J Clin Endocrinol Metab 2008;93:4969-73.  Back to cited text no. 94
Tinahones FJ, Murri-Pierri M, Garrido-Sánchez L, García-Almeida JM, García-Serrano S, García-Arnés J, et al. Oxidative stress in severely obese persons is greater in those with insulin resistance. Obesity 2009;17:240-6.  Back to cited text no. 95
Hardy OT, Perugini RA, Nicoloro SM, Gallagher-Dorval K, Puri V, Straubhaar J, et al. Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity. Surg Obes Relat Dis 2011;7:60-7.  Back to cited text no. 96
Uzun H, Konukoglu D, Gelisgen R, Zengin K, Taskin M. Plasma protein carbonyl and thiol stress before and after laparoscopic gastric banding in morbidly obese patients. Obes Surg 2007;17:1367-73.  Back to cited text no. 97
Klöting N, Fasshauer M, Dietrich A, Kovacs P, Schön MR, Kern M, et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 2010;299:E506-15.  Back to cited text no. 98
Qatanani M, Tan Y, Dobrin R, Greenawalt DM, Hu G, Zhao W, et al. Inverse regulation of inflammation and mitochondrial function in adipose tissue defines extreme insulin sensitivity in morbidly obese patients. Diabetes 2013;62:855-63.  Back to cited text no. 99
Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM. Increased malonyl-coa levels in muscle from obese and Type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 2006;55:2277-85.  Back to cited text no. 100
Sriwijitkamol A, Coletta DK, Wajcberg E, Balbontin GB, Reyna SM, Barrientes J, et al. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with Type 2 diabetes. Diabetes 2007;56:836-48.  Back to cited text no. 101
Sag D, Carling D, Stout RD, Suttles J. Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 2008;181:8633-41.  Back to cited text no. 102
Yang Z, Kahn BB, Shi H, Xue B. Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J Biol Chem 2010;285:19051-9.  Back to cited text no. 103
Pilon G, Dallaire P, Marette A. Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: A new mechanism of action of insulin-sensitizing drugs. J Biol Chem 2004;279:20767-74.  Back to cited text no. 104
MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Ann Rev Immunol 2013;31:259-83.  Back to cited text no. 105
Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. AMPK activation: A therapeutic target for Type 2 diabetes? Diabetes Metab Syndr Obes 2014;7:241-53.  Back to cited text no. 106
Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: Implications for human health and disease. Biochem J 2009;418:261-75.  Back to cited text no. 107
Winder WW, Hardie DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol Endocrinol Metab 1996;270:E299-304.  Back to cited text no. 108
Chen ZP, Stephens TJ, Murthy S, Canny BJ, Hargreaves M, Witters LA, et al. Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 2003;52:2205-12.  Back to cited text no. 109
Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ. Evidence for 5'AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 1998;47:1369-73.  Back to cited text no. 110
Lantier L, Fentz J, Mounier R, Leclerc J, Treebak JT, Pehmøller C, et al. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J 2014;28:3211-24.  Back to cited text no. 111
Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jørgensen SB, Schertzer JD, et al. AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci 2011;108:16092-7.  Back to cited text no. 112
Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: Old or new insights? Diabetologia 2013;56:1898-906.  Back to cited text no. 113
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in Type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American diabetes association and the European association for the study of diabetes. Diabetes Care 2015;38:140-9.  Back to cited text no. 114
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348:607-14.  Back to cited text no. 115
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig 2001;108:1167-74.  Back to cited text no. 116
Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Investig 2010;120:2355-69.  Back to cited text no. 117
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013;494:256-60.  Back to cited text no. 118
Fryer LG, Parbu-Patel A, Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002;277:25226-32.  Back to cited text no. 119
LeBrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, et al. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am J Physiol Endocrinol Metab 2006;291:E175-81.  Back to cited text no. 120
Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun 2004;314:580-5.  Back to cited text no. 121
Hwang JI, Yun S, Moon MJ, Park CR, Seong JY. Molecular evolution of gpcrs: GLP1/GLP1 receptors. J Mol Endocrinol 2014;52:T15-27.  Back to cited text no. 122
Lee J, Hong SW, Chae SW, Kim DH, Choi JH, Bae JC, et al. Exendin-4 Improves steatohepatitis by increasing sirt1 expression in high-fat diet-induced obese C57BL/6J mice. PLoS One 2012;7:e31394.  Back to cited text no. 123
Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, de Minicis S, Candelaresi C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011;31:1285-97.  Back to cited text no. 124


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Regulation of AM...
Plethora of AMP-...
Role of AMP-Acti...
Relevance of AMP...
Article Figures

 Article Access Statistics
    PDF Downloaded191    
    Comments [Add]    

Recommend this journal