TheinsulinresistanceoftypeIIdiabetesappearstobecausedinpartbythepresenceofhighlevelsoflipidsincellssuchasskeletalmusclewherethiswouldnotnormallybefound.Thepresenceofexcesslipidstoresinskeletalmusclecellsinterfereswithenergymetabolism,impairingglucoseoxidationandinsulinresponse.Skeletalmuscleisoneoftheprimaryglucose-consumingtissues,givingitacentralroleininsulinresistance.Theincreasedriskofdiabetesassociatedwithobesitymaybecausedbyincreasedlipiddepositsinskeletalmuscleandliver,creatinginsulinresistance.LeptinisapeptidehormonesecretedbyADIposetissuethathasbeenassociatedwithmanyprocesses.Oneofthetargettissuesofleptinisthehypothalamuswhereitcanacttoregulatefeedingbehaviorandmetabolism.Anotherleptintargetisskeletalmuscle.ActivationofleptinsignalinginskeletalmuscleactivatestheAMP-activatedproteinkinase(AMP-kinase),knowntoplayakeyroleinsignalinginresponsetonutrientsthroughoutevolution(SeeAMPKpathwayandSnf1pathway).AMPKphosphorylatesandinactivatestheenzymeACC,acetyl-CoAcarboxylase.ACCcatalyzestheproductionofmalonyl-CoAfromacetyl-CoA.Malonyl-CoAinturnisaninhibitoroftheimportoffattyacidsintomitochondriabycarnitinepalmitoyl-transferaseIforoxidationandenergyproduction(SeeMitochondrialcarnitinepalmitoyl-transferasepathway).Inthepresenceofleptin,AMPKisactivated,ACCisinhibited,andmalonyl-CoAlevelsfall,increasingtheoxidationoffattyacidsandreducingthelipidcontentofcells.Thereducedlipidcontentinskeletalmuscleallowsinsulinsignalingandglucoseconsumptiontoreturntotheirnormallevels,reducinginsulinresistance.

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REFERENCES:Greco,A.V.(2002)InsulinResistanceinMorbidObesity:ReversalWithIntramyocellularFatDepletion.Diabetes51(1),144-151Minokoshi,Y.etal.(2002)Leptinstimulatesfatty-acidoxidationbyactivatingAMP-activatedproteinkinase.Nature415(6869),339-43Winder,W.W.(2001)Energy-sensingandsignalingbyAMP-activatedproteinkinaseinskeletalmuscle.J.Appl.Physiol.91(3),1017-28

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