The Role of Melatonin in Diabetes: Therapeutic Implications

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Arch Metab. Endocrinol 2015;59/5 lin levelsindiabetic animalsandhumans (6). Pinealec insu of bloodglucoseduetomelatonin andincreased profiles thediurnal Experimental evidencesproposed by thepinealglandlocallyin severalothertissues(4,5). phan derived small indolic molecule, is mainlysecreted atrypto Melatonin (N-acetyl-5-methoxytryptamine), sulin, onbloodglucoseandcarbohydratemetabolism. ofin onthesecretion ofpinealhormone the effect ofdiabetes(3). favors theoccurrence patterns rhythms (2).Deviationincircadian circadian disturbance ofthesleep/wakecyclealongwithother andintakeofexcessivelyrichdiets,cause nocturnality suchasatendencyto cemia). Changinglifestyletrends utilizeinsulinhencepatientshavehypergly or properly enough thebody’sinabilitytoproduce from resulting ing hyperglycemia) andtype2(ametabolicdisorder caus younger patientswithalackofinsulinproduction two maincategories:type1(anautoimmunediseaseof (1).Diabetesisclassifiedinto effect duced incretin D INTRODUCTION man pancreaticisletsmayhaveanimpactonpharmacotherapyoftype2diabetes. be restoredbymelatoninsupplementation. onhu Therefore, thepresenceofmelatoninreceptors turbance ofinternalcircadiansysteminducesglucoseintoleranceandinsulinresistance,which could production ofinsulingrowthfactorandpromotesreceptortyrosinephosphorylation. The dis observed indiabeticpatients.Evidencesfromexperimentalstudiesproved thatmelatonininduces reduction inmelatoninlevelsandafunctionalinterrelationship betweenmelatoninandinsulinwas inducingaphaseshifttors inthecells.Melatoninmaybeinvolved inthegenesisofdiabetesasa cAMP andcGMPpathwaysthephospholipaseC/IP3pathway, butactivates which mobilizes Ca (MT1andMT2).Itdecreasesinsulinsecretionbyinhibiting diated throughthemelatoninreceptors elevated duringnightandlowtheday. The effects ofmelatoninoninsulinsecretionareme Melatonin referred asthehormoneofdarknessismainlysecretedbypinealgland,itslevelsbeing ABSTRACT Shweta Sharma therapeutic implications The role ofmelatoninindiabetes: function, abnormally highglucagonlevelsandare function, abnormally by thepancreaticisletsinacircadianmanner, isduetothemelatoninactiononrecep organelles andinvitro,insulinsecretion and,consequentlyincreasesinsulinsecretion.Bothinvivo Melatonin; diabetes;insulin;betacells;calcium;circadianrhythm Keywords 2015;59(5):391-9 Priyanka Mishra Inconsistent data have been reported concerning concerning Inconsistent datahavebeenreported lin resistance, a diminished pancreatic beta-cell adiminishedpancreatic lin resistance, iabetes isanendocrinedisease,consistofinsu 1 1 , HemantSingh ,Archana Tiwari 1 , Ahmad Nabeel 1 2 , ------ptamine, 5-HT), further acety ptamine, 5-HT), further (5-hydroxytry serotonin into initially theconversionofamino acidtryptophan logical clock(15).Itssynthesis comprisedoftwosteps, oscillationsofthe bio adjust thetimingorreinforces mL) (14).Itmaintainshomeostasis inthebody, helps 100 pg/mL) and low levels during the day (10–20 pg/ centration inplasmaduringnightwasfoundtobe(80– bythepineal gland.Inmammals,thecon secreted are plasma concentrations Circulating thoxytryptamine. indoleamine with the chemical name N-acetyl-5-me ofdarkness,isan Melatonin isknownasthehormone MELATONIN ANDITSFUNCTION orboth. ofinsulinsecretion, improvement insulinsensitizationorby eitherbyimproving effect Melatonin canbeabletobringanti-hyperglycemic blood glucose concentration and type 2 diabetes (8-13). 2(MTNR1B)locusislinkedwith anincreased receptor cific single-nucleotidepolymorphismsofthemelatonin Genome-wide association studies has shown that spe intype2diabeticGotoKakizakirats(6). is observed melatoninandhigherinsulinlevel inserum reduction ver, diabetes is coupled with lower melatonin levels as causeshyperinsulinemia(7).Moreo tomy ofrodents Arch Endocrinol Metab. 2+ from - - - - Rajput, Uttar Pradesh IFTM University, Lodhipur Nagar, Bhopal,Madhya Pradesh Gandhi Technical University, Gandhi Accepted onJuly/6/2015 Received onJune/8/2015 [email protected] 462036 –Bhopal,Madhya Pradesh Airport BypassRoad, GandhiNagar Rajiv Gandhi Technical University School ofBiotechnology Shweta Sharma Correspondence to: 2 1 DOI: 10.1590/2359-3997000000098 School ofBiotechnology, School ofBiotechnology, Rajiv review 391 ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. Clock, Dbp; ------>-indirect effect.B) Graphicalrepresentation (ofvariationinmelatoninlevel atdifferenttimeoftheday. kinase C;MSK1: MAPKsignaling pathway;CREB: cyclic AMP responsive elementbindingprotein;ClockgenesincludePer, Cry, Dec, Rev-erba, Bmal1, activator; AC: adenylatecyclase; PLC: phospholipase C; cAMP: cyclicadenosine monophosphate; DAG: diacyl glycerol; PKA: protein kinase A; PKC: protein 392 melatonin receptortype1A;MT2: melatoninreceptortype1B;G Figure 1. (A)Schematicrepresentationofthemelatonin secretionandsignalingmechanisminmaintainingcircadianrhythm withinthecell. MT1: andheat loss via effect nistration induceshypothermic melatoninadmi effect; asasleep-promoting sidered activity, ofcircadian ordination whichisgenerallycon rhythm. and thusmaintaincircadian ofClock genes expression CREB andMSK1regulates ly. kinases, activityofprotein Duetophosphorylating itactivatesG with melatoninreceptors, the nighttime,itisstimulated.Whenmelatoninbinds the day, is inhibited while at melatonin production totheeyes.During or deactivatedbylightexposure rhythm withinthecell.Thepinealglandisactivated inmaintainingcircadian melatoninreceptors through and signaling pathway illustrates melatonin secretion 1 melatonin.Figure cytes inthepinealglandsecrete dole-O-methyltransferase (HIOMT)(16).Pinealo intomelatoninbyhydroxyin finally beingconverted the rate-limiting step in melatonin biosynthesis, before N-acetyltransferase(AA-NAT), lation byarylalkylamine Melatonin andtype2diabetes and activatesphospholipaseC/IP inhibitadenylatecyclase/cAMP pathway which inturn Melatonin hasseveralfunctionsrangingfrom A B 3 pathway respective i and G q proteins proteins i : guaninenucleotidebinding protein (adenylatecyclaseinhibitor);G co ------the distalskinregions (IRS-1) through MT2signaling(27).Hepatocytes ex (IRS-1) through substrate-1 ofinsulinreceptor cells byphosphorylation lation (26).Italsostimulatesglucoseuptakeinmuscle dent glucose transporter, Glut4, after melatonin stimu oftheinsulin-depen expression been showntoreduce MT2andhave a majortarget tissueforinsulin,express withinsulin(23).Moreover,shared humanadipocytes, similartotheaction cortex, (25) intheadrenal secretion (24).Itlowerscortisol theMT2receptors tion through theMT1andvasodila about vasoconstrictionthrough target tissues(22,23).Inaddition,melatoninbrings autocrine/paracrinefashionnear orinamore hormone levelsofthe thecirculating (21),through its receptors activation of both through itseffects exerts hormone enzymes (19)andactsonbonemetabolism(20).The cycles (18). toold folk. (17); stabilize sleep-wake younger children cadian rhythmaswellinhealthyindividuals,from glucose release from theliverinmice(28). from glucose release andmelatonininjectionselevated MT2receptors press Melatonin stimulatesseveralantioxidative in persons with disrupted cir in personswithdisrupted Arch Metab. Endocrinol 2015;59/5 q : phospholipaseC - - - - - Arch Metab. Endocrinol 2015;59/5 were examinedby output genes, DbpandRev-erbαwere aswellclock-controlled Per1, Per2,ClockandCry1 tional level(38).Duringa24-hr period,Tim,Bmal1, ofclockgenes on thetranscrip changing theexpression analyzedby insulinoscillations were circadian creatic 1and (Cry 2, and3)Cryptochrome transcription oftarget genes,includingPeriod(Per1, andactivate also knownasBmal1)thatheterodimerize nuclear translocator-like receptor , hydrocarbon (Arntl (Clock)andAryl regulator including theclockcircadian tains rhythmicfunctionsconsistoftheclockregulators and obesity(36).Thetranscriptionfactorsthatmain includingdiabetes the instanceofmetabolicsyndrome, systemisassociatedwith ofthecircadian Deregulation MELATONIN ANDCIRCADIAN RHYTHM tissue (35). gerhans andalsoinhumanpancreatic MT1 and MT2 in the islets of Lan melatonin receptors ofthe thepresence nocytochemical studiesconfirmed insulin rhythm(34).Moreover, molecularandimmu on the as isolated islets of rats has phase-shifting effects atic onthepancre rat islets.TheexistenceofMT2receptor neonatal ofinsulin from melatonin actiononsecretion antagonist luzindole (33), both of which inhibit the nosine 5’-O-(3-thiotrisphosphate)andthemelatonin sable guanosine-5’-trisphosphate(GTP)analoguegua experimentsvia non-hydroly β-cells asconcludedfrom (32). quinone reductases ist andhasbeenidentifiedthatbelongtothefamilyof supposedtoex melatoninreceptor MTNR1B), athird 2(MT2; (MT1; MTNR1A)andmelatoninreceptor 1 found in humans, melatonin receptor tonin receptors mainlytwotypesofmela are homology (31).There of exhibitahighdegree (30,31). Thetworeceptors knownasMel1aandMel1b MT1 andMT2previously denoted transmitted viatwoknownGPCRisoforms, All of its cellular actions and effects effects. both receptor-independent andreceptor-dependent soit able substanceowingtoitschemicalstructure asmembrane-perme Melatoninisconsidered surface. on the cell ological functions via membrane receptors rhythmsandotherphysi Melatonin mediatescircadian (GPCR)(29). coupledreceptors toasGprotein ferred re belongtoafamilyofreceptors Melatonin receptors CLASSIFICATION MELATONIN RECEPTORSANDITS The melatonininfluencesexocytosisofinsulinby β-cell isaccomplishedbyapplicationofmelatonin 2) (37).Pan are likely are has ------existence of a circadian oscillatorwithinislets.Inaddi existence ofacircadian andthe pacemakerintheratpancreas ofacircadian role RT-PCRreal-time establishedthe (39,40).Theresults the pancreas or indirectly viatheSCN. orindirectly the pancreas in influencetheclockmachinery could eitherdirectly of glucosehomeostasis(45).Inthismanner, melatonin regulation role ofperipheralclocksinthe signifies akey inisletsizeandsurvival, anddecreases sulin secretion and Clock ofpancreatic (43).Theremoval was reintroduced oncetheclockprotein condition whichwasreversible showed lackofrhythmicityintheactioninsulin,a (43,44). Inanexperiment,studyClock system bycircadian glucose metabolismisregulated cadian rhythms.Likewiseotherphysiological functions, peripheraltissues,thusmaintainingcir tors ofdifferent cesses (41,42). metabolicpro thatcontrol adipose tissue,andpancreas peripheraltissuesincludingtheliver,numerous white tion to the SCN, clock activities have been identified in activated PKG can directly phosphorylate andpoten phosphorylate activated PKG candirectly kinase G(PKG).The GMP (cGMP)-dependentprotein Itactivatescyclic MT2receptors. clase (sGC)through NO-inducible,solubleguanylate cy negatively affects pancreatic insulin through of secretion second messenger cGMP and suppresses MT1receptors. protein-coupled mediatedviaGi whichare stimulated insulinsecretion, thatmelatonininhibitscAMP- confirmed These results nin onthelevelsofcAMPandinsulinaswell(48). ofmelato toxin(PTX)abolishedtheeffect pertussis ofmelatonin(33).TheGiα-protein-inhibitor effects thecAMP-andinsulindiminishing pletely reversed antagonistslikeluzindolecom found thatreceptor itwas skolin, adenylylcyclaseactivator(48).Previously stimulatedbyfor The insulinandcAMPlevelswere islets of neonate rats (33,46,47). isolated pancreatic from as wellforskolin-stimulatedinsulinsecretion islets and the rat insulinoma pancreatic in incAMP production isreduction to melatoninthere 2.Due shownin figure and IP3-signalingpathwaysare includescAMP-,cGMP-, MT2-membrane receptors pancreatic The intracellularsignaltransductionpathwaysofthe MELATONIN SIGNALINGINPANCREATIC b-CELLS Melatonin exerts its effect through melatoninrecep through itseffect Melatonin exerts Melatonin activates MT2 receptor that inhibits the thatinhibitsthe Melatonin activatesMT2receptor in mice resulted infunctionaldefects Bmal1 inmiceresulted β-cell influencedbymelatoninviaMT1-and β -cells (49,50). Melatonin andtype2diabetes β-cell line INS1, mutant mice Melatonin Melatonin 393 ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 394 (B) thecGMPpathway, (C)thephospholipase C/IP Figure 2. Hypotheticaldiagramfortheeffectof melatoninonpancreaticβ-cellsviadifferentsignalingpathways; (A)theadenylylcyclase/cAMPpathway, A ner, antago during the same time melatonin receptor tonin stimulatedIP 2Aand2B). cGMP-specific phosphodiesterases(Figures target oncyclicnucleotide-gated(CNG)channelsand rhythms.cGMPsignalingcascadealso ting ofsecretion inhibiting activatingbmal1/clockandantagonistic, erodimeric, clockgenes(e.g.onhet circadian modulates pancreatic Via PKG, cGMPprobably diated influenceonCREs. me both cAMPandcGMPpathwaysmayhavereceptor manner.second messengercAMPinaninhibitory Thus, cer-binding onCREBand/orC/EBP(CCAATtially turns enhan Melatonin andtype2diabetes In theexperimentinvolvingINS1cellline,mela genes)leadstophase-shifting/reset cry/per1 protein. The MT2-receptor also affects the the alsoaffects TheMT2-receptor protein. 3 release inadosedependentman release C 3 pathway. ------

role of melatonin receptors (51).Inaddition,mela ofmelatoninreceptors role (PKC) and increased vesicle fusion (Figure 2C). vesiclefusion(Figure (PKC) andincreased kinaseC kinaseD(PKD),protein activation ofprotein (DAG), mayleadtoMAPKp38-modulated glycerol phate (IP markedlyelevatinginositoltriphos via Gqproteins, ing pathwayofmelatoninstimulatesphospholipaseC tonin inducedIP IP nist luzindolewascapableofabsolutelyinhibitingsuch β-cell. Alternatively, MT2-receptor-dependent signal bypancreatic mechanism thattriggersinsulinsecretion (51),acommon intracellularstores into thecellfrom co-product ofphospholipaseC(PLC)activity,co-product diacyl B 3 -liberating effects of melatonin, hence signifying the -liberating effects 3 )/Ca 2+ from intracellular stores (52-54).The intracellularstores from 3 liberationthatallowCa Arch Metab. Endocrinol 2015;59/5 2+ to flow - - - - Arch Metab. Endocrinol 2015;59/5 concentration of plasma glucose. Since the intake of variationinthe oftheactivephaseshows circadian start atthe atic isletcells.Highlevelof glucoseobserved ofinsulinandglucagonbythepancre is thesecretion (6,66).Thebasis forglucose homeostasis the pancreas thefunctionof levels ofdiabeticpatientscould affect melatonin biochemical basistoexplainhowdecreased a andprovides ence insulinorglucagonproduction influ that theiractivationbymelatoninmightdirectly isletsproposes in the pancreatic of melatonin receptors (10,35,53,55,61-65).Theoccurrence MT2 receptors MT1and celllineshasbeenfoundtoexpress rodent tissuesandislets pancreatic Human androdent MELATONIN ANDINSULINSECRETION glucosetoleranceandinsulinsensitivity (60). reduced postmenopausal women as administration of melatonin selected populationof sented bythedataobtainedfrom pre tion (59).Clinicalimplicationsofmelatoninwere ininsulin secre toincrease the mechanismnotrelated FPG(fastingplasmaglucose)but decreasing through glycemiccontrol improved with andwithoutmetformin tients, whenmelatoninandzincacetatesupplemented oftype 2diabeticpa (Glut1 and2)(58).Inagroup andhepaticglucosetransporters dition topancreatic inad islet hormones on transcriptlevelsofpancreatic deficiencyhaveaneffect lished thatmelatoninreceptor estab Reverse transcriptionpolymerasechainreaction inβ sensitizer andbyimprovement inyoungZDFratsasinsulin anti-hyperglycemic effect diabetes, showthatoralmelatoninadministrationexert andtype2 perimental modelofmetabolicsyndrome in youngmaleZuckerdiabeticfatty(ZDF)rats,anex ofmelatonin on glucose homeostasis gating the effects the developmentoftype2diabetes.Thestudyinvesti ofmelatoninmightbeassociatedwith the insufficiency inbloodand glycemiccontrol that melatoninimproves indicate of type2diabetes(56).Theseclinicalresults blood glucose level and susceptibility to theoccurrence linkedwithfasting genewere the melatoninreceptor (55). Furthermore, was observed of melatonin membrane receptor mRNA expression type 2diabetes(11),atthesametimeupregulated melatoninoccurinpatientswith quantity ofcirculating and glucose homeostasis. A low ence insulin secretion Various studieshaveshownthatmelatoninmayinflu MELATONIN ANDGLUCOSEHOMEOSTASIS -cell function (57). -cell function(57). polymorphisms in polymorphisms in ------(11,61). Thetwo commongeneticvariants: rs1387153 risk of type 2 diabetes glucose levels or the increased human pancreatic islet cells have beenfoundtopos human pancreatic exhibit a daily rhythm as well. In contrast, mouse and in plasmafollowthedailyrhythmfeedingandmay theamountofinsulin food inducesinsulinsecretion, (70,71). elevated whenmelatoninlevelsare measured levels are of night, low levels of insulin along with high glucose inratsduringthedaywhile atthetime insulin secretion Moreover, inmelatoninlevelsaugmented thedecrease (69). anddifferentiation) growth cell proliferation, with cellmetabolism)andMEK/ERKs(involvedin intracellular signalingpathways:PI3K/AKT(involved (69).Itactivatestwo phosphorylation (IR) tyrosine (IGF-R)andinsulinreceptor factorreceptor growth cellsbystimulatinginsulin ofpancreatic differentiation and growth noblotting shownthatmelatoninregulate and immu islet by immunoprecipitation pancreatic function.Theanalysisofmelatoninon over pancreatic regulation ofacircadian gives emphasistothepresence activityaswell(34,67,68).Thisconcept sess circadian within studies (GWAS) identifiedcommongeneticvariants islets creatic in human pan tors have been found to be expressed type1B.Thetwodistinctrecep melatonin receptor type1Aand melatoninreceptor tein coupledreceptors, bythetwoG-pro ofmelatoninisexerted The effect MELATONIN RECEPTORPOLYMORPHISM betes. both on insulin secretion effect direct orin ofmelatoninhavedirect thatpresence proposed the available literature glucose uptake (73). Therefore, meostasis inmiceandmightstimulateinsulintoinduce involvedinthemodulationofglucoseho are receptors type 2diabetesdevelopment(44). couldbeacriticalfactorfor lightexposure nocturnal by ofmelatonin secretion of insulin(72).Suppression cellsemphasizingitsactivityinthefunction pancreatic of insulinfrom tonin inhibitsglucosemediatedrelease tional toplasmamelatoninconcentration(72).Mela isinversely propor the findingsthatinsulinsecretion tion betweenmelatoninandtype2diabetesbasedon night-time insulin concentrations in patients with dia associatedto vitro, andnight-timemelatoninlevelsare There is prospect that there mightbeanassocia thatthere isprospect There MTNR1B (23,64). Recentgenome-wide association were associated withhigherfasting were Melatonin andtype2diabetes Furthermore, MT1 Furthermore, in vivo and 395 in ------

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 396 and a functional inter-relationship between melatonin inmelatoninlevels In diabeticpatients,areduction MELATONIN AND DIABETES (86). cohorts inGerman cretion Single Nucleotide Polymorphisms thattheMTNR1B-associated reported of researchers CRY2 apolymorphicallelewasidentified in Furthermore, during the oral glucose-tolerance test (84). processing with FPG(Fastingplasmaglucose)levelsandglucose subjects, mellitus) and,innon-diabeticnormoglycemic riskofdevelopingGDM(Gestational diabetes creased rs10830963 inMTNR1B thatalleleGof of women confirms on a Czech cohort when stratifiedbyIGRoutcome(83).Anotherstudy glucose tolerance) glucose) butnotforIGT(impaired fasting rs10830963 polymorphism for IGF(impaired riskofMTNR1B as indicatedsignificantlyincreased ofsusceptiblegeneticvariationsaswell background might have similar glucose regulation) (Impaired hyperglycemia (61).OnestudysuggestedthatIGR andthereby atic glucosesensingandinsulinsecretion pancre plies thatMTNR1Bgenevariantmightaffect (82). lation ofglucosehomeostasisduringpregnancy involved intheregu tolerance soMTNR1Bisprobably (75-80), JapaneseandSriLankanpopulations(81). inAsianadults,includingChinese reported tes were the elevated fasting glucose and risk of type 2 diabe (11,74). Recently, the associationsofrs10830963with risk oftype2diabetesbythers10830963allele thepathomechanismforincreased might represent and beta cell dysfunction that early insulin secretion of to impairment (12). The risk allele was also related risktodevelopdiabetes associated withanincreased associated withfastingglucoselevelsandmoderately thatrs10830963isstrongly A meta-analysisrevealed nucleotide polymorphism(SNP)rs10830963(74). associationsignalwasthesingle ant withthestrongest of melatonin. The vari that encodestheMT2receptor located near the gene and rs10830963 are Melatonin andtype2diabetes were showntobeassociatedwithgestationalglucosein were rs10830963, rs1387153,rs2166706andrs1447352 Chinesewomen,theMTNR1B variant the pregnant concentrations in the blood and decreased insulin se concentrations in the blood anddecreased all significantlyassociatedwithhigherfastingglucose rs10830963 were rs4753426 and the aforementioned The expression of MT2 receptor intheβ-cellsim ofMT2receptor The expression associated with type 2 diabetes (85). A group associated withtype2diabetes(85).Agroup gene isassociatedwithin rs10830962, MTNR1B

In ------perhaps beinvolvedin the genesisof diabetes (6). Onthisbasismelatoninmay and insulinwasobserved. with diabetes mannerhasbeenrelated melatonin levelinirregular fashiontomelatonin(94). Decreased alters inareverse tion betweenmelatoninandinsulini.e.levels isnegativecorrela rhythmbutthere exhibit acircadian type 2diabetes(11,92,93).Bothmelatoninandinsulin andriskof insulinsecretion, levels inplasma,impaired glycemictraitssuchaselevatedfastingglucose affect MT2 that allelicvariationsofthemelatoninreceptor (91). Genome-wide association studies have proposed ofhighfatdietintakeinrats of clockgenesasaresult bythealterationof24hrhythmicexpression proved tween glucose and time keeping mechanism has been 2 diabetes(88-90).Theexistenceofanassociationbe glucosetoleranceandtype riskforadecreased greater anda betweensleepdisorders established acorrelation intheevening(87).Inaddition,variousstudies served whiledeclineininsulinsensitivitywasob of morning atthetime insulinrelease erance mainlybydecreasing homeostasis and body weight regulation under certain undercertain homeostasis and bodyweightregulation onglucose supplementation mayhavebeneficial effects animalstudiessuggestthatmelatonin insulin. Different beta-cell functionanddeclinein sive loss ofpancreatic progres from type2 diabetes andtypicallyresult from complicationsthatarise evations offastingglucoseare andsubstantialel tance. Thelossof glycemic control of hyperglycemia and insulin ing resis the prevalence system maybeatractabletarget fordecreas Circadian CONCLUSION or developmentoftype2diabetes. to lightatnightandaging,mayleadtheoccurrence Hence, ofLDchanges(97). of clockfunctioningasaresult duetomisalignment behavior andinsulinlevelsare glucose levelsofratssuggestingthatthechangesin larger variationsinblood were diabetes (97).There in rats with no shift was observed conditions whereas theLD(light/dark) onreversing observed rats were blood glucoseanddonotexistinhealthyhumans(96). rhythm thatimpel fasting high duction exhibit circadian diabetes, gluconeogenesisandendogenousglucosepro maintaining homeostasis in blood and nin signal is critical for glucose regulation humans, melatonin administration reduced glucosetol humans, melatonin administration reduced Significant changes in behavioral activity in control Significant changesinbehavioralactivitycontrol the decline in melatonin levels during exposure the declineinmelatoninlevelsduringexposure (6,55), whichsuggeststhatthemelato (95). Inpatientswithtype2 Arch Metab. Endocrinol 2015;59/5

In ------can improve β-cellfunction,somelatoninsupplemen can improve Arch Metab. Endocrinol 2015;59/5 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES rhythm. scribed forsleepandcircadian pre whichiscurrently thediabeteseffects to overcome therapeuticstrategy sis. Itwouldadvancethecurrent onglucosehomeosta tation mayhavebeneficialeffects by IP duces insulin secretion evidencethatmelatoninin clinical issue.Thepresent mal levelsofbloodsugar middle-aged andolderadultsmaintenanceofopti diseasein indiabetes.Diabetesis a prevalent hormone in humanstoevaluatethetherapeuticpotentialofthis whichshouldencourageclinicaltrials circumstances, ant in MTNR1B, encoding melatonin receptor 1B, is associated 1B, ant inMTNR1B,encodingmelatonin receptor Rönn T, Wen J, Yang Z, LuB, Du Y, GroopL,et al. 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