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Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.ch

Year: 2012

PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucosehomeostasis

Schultze, S M; Hemmings, B A; Niessen, M; Tschopp, O

Abstract: New therapeutic approaches to counter the increasing prevalence of obesity and type 2 diabetesmellitus are in high demand. Deregulation of the phosphoinositide-3-kinase (PI3K)/v-akt murine thy-moma viral oncogene homologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activatedprotein kinase (AMPK) pathways, which are essential for glucose homeostasis, often results in obesityand diabetes. Thus, these pathways should be attractive therapeutic targets. However, with the excep-tion of metformin, which is considered to function mainly by activating AMPK, no treatment for themetabolic syndrome based on targeting protein kinases has yet been developed. By contrast, therapiesbased on the inhibition of the PI3K/AKT and MAPK pathways are already successful in the treatmentof diverse cancer types and inflammatory diseases. This contradiction prompted us to review the signaltransduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles in glucose homeostasis, andwe also discuss current clinical implications.

DOI: https://doi.org/10.1017/S1462399411002109

Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-56698Journal ArticlePublished Version

Originally published at:Schultze, S M; Hemmings, B A; Niessen, M; Tschopp, O (2012). PI3K/AKT, MAPK and AMPKsignalling: protein kinases in glucose homeostasis. Expert Reviews in Molecular Medicine, 14:e1.DOI: https://doi.org/10.1017/S1462399411002109

https://doi.org/10.1017/S1462399411002109https://doi.org/10.5167/uzh-56698https://doi.org/10.1017/S1462399411002109

PI3K/AKT, MAPK and AMPK

signalling: protein kinases in

glucose homeostasis

Simon M. Schultze1,2, Brian A. Hemmings2, Markus Niessen1

and Oliver Tschopp1,*

New therapeutic approaches to counter the increasing prevalence of obesityand type 2 diabetes mellitus are in high demand. Deregulation of thephosphoinositide-3-kinase (PI3K)/v-akt murine thymoma viral oncogenehomologue (AKT), mitogen-activated protein kinase (MAPK) and AMP-activatedprotein kinase (AMPK) pathways, which are essential for glucose homeostasis,often results in obesity and diabetes. Thus, these pathways should be attractivetherapeutic targets. However, with the exception of metformin, which isconsidered to function mainly by activating AMPK, no treatment for themetabolic syndrome based on targeting protein kinases has yet beendeveloped. By contrast, therapies based on the inhibition of the PI3K/AKT andMAPK pathways are already successful in the treatment of diverse cancer typesand inflammatory diseases. This contradiction prompted us to review the signaltransduction mechanisms of PI3K/AKT, MAPK and AMPK and their roles inglucose homeostasis, and we also discuss current clinical implications.

Metabolic syndrome is generally defined as acluster of risk factors for cardiovascular diseaseand type 2 diabetes mellitus (T2DM) includingcentral obesity, arterial hypertension,dyslipidaemia and elevated fasting glucose(Ref. 1). Impaired glucose homeostasis, asobserved in patients with metabolic syndrome,frequently progresses to overt T2DM, which in2010 affected 344 million patients worldwide(Ref. 2). Hyperglycaemia in diabetic patients canlead to life-threatening complications such as

coronary heart disease, stroke and nonalcoholicfatty liver disease (Refs 3, 4, 5).

Strict control of the level of circulating glucosewithin a narrow physiological range suppliessufficient energy for organs and avoidshyperglycaemia. Glucose homeostasis is largelymaintained by the insulinglucagon system,which compensates for physiologicalfluctuations in blood glucose caused by foodintake and physical activity, or by stressconditions such as hypoxia and inflammation.

1Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich,Switzerland2Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

*Corresponding author: Oliver Tschopp, Division of Endocrinology, Diabetes and Clinical Nutrition,University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: oliver.tschopp@usz.ch

expert reviewshttp://www.expertreviews.org/ in molecular medicine

1Accession information: doi:10.1017/S1462399411002109; Vol. 14; e1; January 2012

Cambridge University Press 2012

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Insulin and glucagon are released from - and -cells, respectively, in the endocrine part of thepancreas. Insulin lowers blood glucose bystimulating glucose uptake and storage(glycogen synthesis and lipogenesis) in skeletalmuscle and adipose tissue. In the liver, insulinblocks the release and neogenesis of glucose andstimulates glucose storage. In addition, insulinstimulates protein synthesis, regulatesmitochondrial biogenesis and blocks autophagy.Glucagon antagonises the action of insulin,mostly in the liver, where it stimulatesgluconeogenesis and thereby increases bloodglucose level. The secretion of insulin andglucagon is regulated in a reciprocal manner,which avoids glycaemic volatility because oftheir opposing effects. It was proposed that theglucose-induced secretion of insulin inhibitsglucagon secretion from -cells in a paracrinemanner (Ref. 6). Furthermore, incretin hormones[e.g. glucagon-like peptide 1 (GLP-1)] secretedpostprandially by the gut potentiate glucose-mediated insulin secretion and block glucagonsecretion (Ref. 7). In addition, physiologicalconditions such as low intracellular energy leveland cellular stress affect whole-body glucosehomeostasis by interfering with insulin action.Signal transduction from a stimulus to the

regulation of cellular processes, including thoseinvolved in glucose homeostasis, is primarilydependent on protein kinase signalling. Onactivation, protein kinases determine the outputof metabolic processes by transcriptional andpost-translational regulation of rate-limitingenzymes, such as glycogen synthase 1(GYS1) and fatty acid synthase (FASN, FAS).The insulin receptor (INSR, IR) activatesvarious downstream pathways that controlenergy homeostasis, includingphosphoinositide-3-kinase (PI3K)/v-akt murinethymoma viral oncogene homologue [AKT, alsoknown as protein kinase B (PKB)] and themitogen-activated protein kinase 3/1 (MAPK3/1, ERK1/2). Whereas the PI3K/AKT pathway isconsidered to be the major effector of metabolicinsulin action, insulin-independent kinases alsocontribute to metabolic control. AMP-activatedprotein kinase (AMPK) is mostly activated bylow intracellular energy levels and inhibitsanabolic processes, stimulates energy-producingcatabolic processes and lowers blood glucoselevel. Because correct functioning of the PI3K/AKT, MAPK and AMPK pathways is essential

for proper metabolic control and theirdysfunction often leads to impaired glucosehomeostasis, these pathways are attractivetherapeutic targets (Refs 8, 9, 10). However,PI3K/AKT, MAPK and AMPK are also involvedin several other fundamental cellular processes,including cell proliferation and survival, andthus global therapeutic modification of theiractivities could induce severe side effects.

Today, specific kinase inhibitors are usedsuccessfully for immunosuppression and in thetreatment of inflammatory disease and diversecancer types. However, because properactivation of the PI3K/AKT pathway is requiredfor insulin action, kinase inhibitors targetingPI3K/AKT and downstream effectors mightimpair metabolic control. Even thoughinappropriate activation of MAPKs, especially ofc-Jun N-terminal kinase (MAPK8, JNK), isconsidered to have a critical role in acquiredinsulin resistance, no therapies based on MAPKsare available so far. The only drug targetingprotein kinase activity that is widely used todayin the treatment of insulin resistance anddiabetes is metformin, which is thought tooperate mainly by activating AMPK. Althoughour understanding of the role of protein kinasesin the regulation of glucose homeostasis hasincreased significantly during the past decade,only limited translation into therapies againstthe metabolic syndrome has occurred. Thepurpose of this present review is to summarisethe signal transduction mechanisms involvingPI3K/AKT, MAPK and AMPK with respect totheir role in glucose homeostasis and to discusscurrent clinical implications.

The PI3KAKT signalling pathway is themajor effector of metabolic insulin actionInsulin is an indispensable regulator of glucosehomeostasis, and T2DM is characterised bypostreceptor insulin resistance combined with -cell failure. Insulin signalling is initiated by thebinding of insulin to the extracellular -subunitsof the heterotetrameric IR. This interactioninduces conformational changes and facilitatesautophosphorylation of tyrosine residues onthe intracellular part of membrane-spanning-subunits. These phosphotyrosines then attracta family of adaptor molecules, the insulinreceptor substrates (IRSs). On interaction withthe IR, IRS proteins themselves are tyrosinephosphorylated, which is partially mediated by

expert reviewshttp://www.expertreviews.org/ in molecular medicine

2Accession information: doi:10.1017/S1462399411002109; Vol. 14; e1; January 2012

Cambridge University Press 2012

PI3K/A

KT,

MAPK

andAMPK

signa

lling

:protein

kina

sesin

gluco

seho

meo

stas

is

t