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 Table of Contents  
REVIEW ARTICLE
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
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cdrp.cdrp_5_21

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  Abstract 


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 2022 Jun 26];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

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  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

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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

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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

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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

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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

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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

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Figure 8: ULK-1-independent regulation of autophagy by AMP-activated protein kinase

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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

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  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]

Metformin

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.

Thiazolidinediones

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.



 
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