Diabetes(Mellitus( Dr(Kawa(A.(Obeid( PhD!Therapeutics!

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1 DiabetesMellitus DrKawaA.Obeid PhDTherapeutics 1 Definitionandabriefintroduction Diabetes mellitus is the most common of the endocrine disorders. It is primarily a disorder of carbohydratemetabolismcharacterisedbyhyperglycaemia,thisisduetoimpairedinsulinsecretion withorwithoutinsulinresistance.however,themetabolicproblemsinproperlytreateddiabetesare relatively easy to control, it is the long?term complications of diabetes that are the main causes of morbidityandmortality.peoplewithdiabetessufferfarmorefromcardiovascularandrenaldisease thanotherpeople,anddiabetesistheprincipalcauseofacquiredblindnessinthewest.mostpeople withdiabetesdonotdiefrommetaboliccrisessuchasketoacidosisbutfromstroke,miorchronicrenal failure.diabetesisassociatedwithobesityandlackofexercise,andthesteadyincreaseinprevalence incommunitieswithmodernlife?style. Type1diabetesisadiseasecharacterisedbythedestructionoftheinsulin?producingpancreaticβ? cells,thedevelopmentofwhichiseitherautoimmunet?cellmediateddestructiontype1a)oridiopathic type1b),usuallydevelopsintheyoungbelowtheageof30.whiletype2diabetesismorecommon abovetheageof40itiscausedbyarelativeinsulindeficiencyandinsulinresistance.symptomsare generally slower in onset and less marked than those of type 1. Two other varieties of non?typical diabetes that may be seen are latent autoimmune diabetes in adults LADA) and maturity?onset diabetesoftheyoungmody). Table&1&T1DM&v&T2DM& 2 Epidemiology Type1diabetesmaypresentatanyage,50 60%ofpatientswithtype1willpresentbefore20years ofage.type2diabetesismuchmorecommonthantype1,accountingfor90%ofpeoplewithdiabetes. Itusuallyoccursinthoseovertheageof40yearsandriseswithageandobesity.Diabetesmellitusis oneofthemostcommonendocrinedisordersaffectingalmost6%oftheworld'spopulation.thenumber ofdiabeticpatientswillreach300millionin

2 & Table&2&Prevalence&of&DM& 3 Aetiology Both genetic and environmental factors are relevant in the development of type 1 diabetes, but the exactrelationshipbetweenthetwoisstillunknown.circulatingisletcellantibodiesicas)arepresent inmorethan70%ofthosewithtype1atthetimeofdiagnosis.familystudieshaveshownthatthe appearanceoficasoftenprecedestheonsetofclinicaldiabetesbyasmuchas3years.type1has beenwidelybelievedtobeadiseaseofclinicallyrapidonset,butthedevelopmentisrelatedtoaslow processofprogressiveimmunologicaldamage.however,itisnotcurrentlypossibletousescreening methods to reliably identify patients who will develop diabetes in the future. The final event that precipitatesclinicaldiabetesmaybecausedbysuddenstresssuchasaninfectionwhenthemassof β?cellsinthepancreasfallsbelow5 10%. About85%ofpeoplewithtype2diabetesareobese.Thishighlightstheclearassociationbetweentype 2 and obesity, with obesity causing insulin resistance. In particular, central obesity, where adipose tissueisdepositedintra?abdominallyratherthansubcutaneously,isassociatedwiththehighestrisk. BodymassindexBMI)hasbeenusedasanindicatorforpredictingtype2risk\however,itdoesnot take fat distribution into account, so waist circumference measurements are now being increasingly used. 2

3 Table&3&Risks&of&developing&DM& Table&4&Etiological&differences&between&T1DM&v&T2DM& 4 Pathophysiology Insulinmolecularweightabout5800Da)iscomposedof51aminoacidsintwochainsof21Achain) and30bchain)aminoacidsconnectedbytwodisulphidebridges.insulinissecretedbyβ?cellsofthe isletsoflangerhans.itlowersbloodglucose,butalsomodulatesthemetabolicdispositionoffatsand aminoacids,aswellascarbohydrate.insulinisstoredingranulesincombinationwithccpeptideas proinsulinmolecularweight9000da),whichissplitbeforereleaseintotheportalvein.insulinhasa plasma half?life of only about 5min. inactive C?peptide, which provides a useful index of insulin secretion: its plasma concentration is low or absent in patients with type 1 diabetes. C?peptide concentrationisnotelevatedinpatientswithhypoglycaemiacausedbyinjectionofinsulin. Glucose is the major stimulant to insulin release. The response is triggered both by the intake of nutrientsandthereleaseofgastro?intestinalpeptidehormones.followinganintravenousinjectionof glucose,thereisabiphasicinsulinresponse.thereisaninitialrapidresponseinthefirst2min,followed after5 10minbyasecondresponsewhichissmallerbutsustainedover1h.Theinitialresponse representsthereleaseofstoredinsulinandthesecondphasereflectsdis?chargeofnewlysynthesised insulin.glucoseisunique\otheragents,includingsulphonylureas,donotresultininsulinbio?synthesis, onlyrelease.oncereleasedfromthepancreas,insulinenterstheportalcirculation.theliverrapidly 3

4 degradesitandonly50%reachestheperipheralcirculation.inthebasalstate,insulinsecretionisata rateofapproximately1unit/h.theintakeoffoodresultsinapromptfive?totenfoldincrease.totaldaily secretionisapproximately40units. Insulincirculatesfreeasamonomer,hasahalf?lifeof3 5minandisprimarilymetabolisedbytheliver andkidneys. Theinteractionofinsulinwiththereceptoronthecellsurfacesetsoffachainofmessengerswithinthe cell.thisopensuptransportprocessesforglucose,aminoacidsandelectrolytes. In type 1 diabetes, there is an acute deficiency of insulin that leads to unrestrained hepatic glycogenolysis and gluconeogenesis with a consequent increase in hepatic glucose output. Also, glucoseuptakeisdecreasedininsulin?sensitivetissuessuchasadiposetissueandmuscle\hence, hyperglycaemiaensues.eitherasaresultofthemetabolicdisturbanceitselforsecondarytoinfection or other acute illness, there is increased secretion of the counter?regulatory hormones glucagon, cortisol, catecholamine and growth hormone. All of these will further increase hepatic glucose production. In type 2 diabetes, the process is usually less acute, since insulin production decreases over a sustainedperiodoftime.hyperinsulinaemiaisabletomaintainglucoselevelsforaperiodoftime,but eventually?cellfunctiondeterioratesandhyperglycaemiaensues.ifthiscycleisnotinterrupted,type2 diabetesdevelops.impairedglucosetoleranceigt),impairedfastingglucoseorhyperinsulinaemia maybedetectedbeforeovertdiabetesdevelops,andifso,astrictdietandexerciseregimenleading toweightlossandimprovedinsulinsensitivitymaydelayorevenpreventtheonsetofdiabetes.atthe timeofdiagnosis,thosewithtype2diabetesmayhavealreadylostabout50%oftheir?cellfunction. Irrespective of treatment, cell function continues to decline with time, often leading to the need for regularinsulintherapy. Figure&1&Factors&affecting&the&release&or&action&of&insulin.&CCK,&cholecystokinin.& &inhibition/antagonismj& o&stimulation/potentiation.&& Figure&2&Schematic&representation&of&normal&diurnal&variations&in&blood&glucose&and&plasma&insulin&levels.& & 4

5 5 ClinicalManifestationsSymptoms) Commonsymptomsincludepolyuriaincreasedurineproduction,particularlynoticeableatnight)and polydipsiaincreasedthirst)accompaniedbyfatigueduetoaninabilitytoutiliseglucoseandmarked weightlossbecauseofthebreak?downofbodyproteinandfatasanalternativeenergysourceto glucose.patientsmayalsoexperienceahigherinfectionrate,especiallycandida,andurinarytract infectionsduetoincreasedurinaryglucoselevels. Type 1 diabetes often associated with diabetic ketoacidosis and the symptoms include nausea, vomiting, dehydration, shortness of breath secondary to an attempt by the respiratory system to neutralisethemetabolicacidosiscausedbytheketonesand,inextremecases,coma. Intype2diabetesPatientsoftenpresentwhenthecomplicationsofsustainedhyperglycaemiahave alreadydeveloped,forexample,cardiovasculardiseaseorrenaldisease.retinopathymaybedetected on routine ophthalmological examination. Alternatively, a combination of neuropathy, peripheral vasculardiseasepvd)andinfectionmaymanifestasfootulcerationorgangrene.insomecases, patientspresentwithhyperosmolarhyperglycaemicstatehhs)whereglucoselevelsinexcessof35 mmol/larefoundandexcessivedehydrationhasoccurred.occasionally,patientswithtype2diabetes presentwithdiabeticketoacidosis. 6 Diagnosis 1. Diabetessymptomsi.e.polyuria,polydipsiaandunexplainedweightloss)plus:fastingserum glucoseconcentration>7.0mmol/lorserumglucoseconcentration>11.1mmol/l2hafter75g anhydrousglucoseinanoralglucosetolerancetest. 2. GlycatedhaemoglobinHbA 1c )isalsonotcurrentlyrecommendedfordiagnosticpurposes, althoughthisiscurrentlybeingconsidered Practice:Glucosetolerancetest Thepatientshouldbefastedfrom8pmexceptforwater)onthedaybeforethetest.Thetestshould commenceataround9amwithavenousserumglucosetest,followedbytheadministrationof75gof glucosebymouthovera5?minperiod.thesecondvenousserumglucosesampleisthentaken2h afterthedrink.thepatientshouldbeseatedandisnotpermittedtosmoke,eatordrinkanythingother thanwateruntilthetestiscomplete.asthereisariskoflater?onsethypoglycaemiainsomeindividuals, itisadvisabletosuggestthatthepatienthassomethingtoeatimmediatelyuponcompletionofthetest, especiallyifhe/sheisplanningtodrive. 7 DiabeticEmergencies Hypoglycaemia and extreme hyperglycaemia, causing diabetic ketoacidosis DKA or hyperosmolar hyperglycaemicstatehhs,constitutethethreeacuteemergenciesassociatedwithdiabetes. 7.1& Hypoglycaemia Hypoglycaemiacanoccurbothwithinsulintreatmentandinthosetakingsomeoralagents,especially thelonger?actingsulphonylureasi.e.glibenclamide)inwhichglucosedropsbelow3.0mmol/l. Neuropathyand blockerscanmaskthesymptomsexposingthepatientstoadifficultcondition.the patient may have recurrent hypoglycaemia. In those individuals who suffer frequent hypoglycaemic episodes,theautonomicsymptomsmayceasetooccur.themostcommoncausesofhypoglycaemia areeitheradecreaseincarbohydrateconsumption,excesscarbohydrateutilisationfromunexpected exerciseorincreaseincirculatinginsulin 5

6 Table&5&symptoms&of&hypoglycaemia&& Nocturnalhypoglycaemia Sometimes,hypoglycaemiaoccursthroughoutthenight.Symptomsmayincluderestlessness,although thismaynotbeidentifiedunlessobservedbyanotherperson.whennocturnalhypoglycaemiaoccurs, the person often wakes feeling unrested, unwell or with a headache. Contrary to what might be expected,morningbloodglucosereadingsmaybehighbecauseasustainedhypoglycaemicepisode leadscounter?regulatoryhormonestoraisebloodglucoselevels.thiscouldpresentaconfusingpicture astheobvioussolutiontoaraisedbloodglucoselevelinthemorningwouldbetoincreasetheevening/ night?time dose of insulin. However, in the case of nocturnal hypoglycaemia, this would make the problemworse.ifnocturnalhypoglycaemiaissuspected,thenbloodglucoseshouldbemeasuredat night,forexample, am.Ifconfirmed,thepatientshouldeitherhaveasnackbeforebedtime, reducetheevening/night?timedoseofinsulin,alterthetimingofadministrationoftheeveningdoseof intermediate? or long? acting insulin in order to delay the peak of bioavailability or change the intermediate?actinginsulintoapeaklessanalogueasappropriate. Treatmentofhypoglycaemia Startwithoralglucoseifpossibleortryeitherintravenousglucoseorintra?muscularglucagon.Inan emergency,hotdrinksshouldbeavoidedastheymightburnanddrinkscontainingmilkarenotsuitable asthefatinmilkslowsdownsugarabsorption.bloodglucoselevelsshouldbemeasuredabout10 15 minaftertreatinghypoglycaemia.ifbelow3.5mmol/l,moreglucoseshouldbeconsumed.ifabove3.5 mmol/landthenextmealwillbeover1h,thenalong?actingcarbohydrateisalsorequired,forexample, breadorbiscuits. Shouldparenteraltreatmentberequired,25gofintravenousglucoseor1mgofintramuscularglucagon isrecommended.glucagontakesapproximately15 20mintowork,butifthepersonhasliverdisease cirrhosis) or is malnourished, then glucagon may not work because glucagon acts by mobilising glucosestoresfromtheliver.insuchcases,intravenousglucosemustbegiven. 7.2& Diabetic+ketoacidosis++ Absenceorseveredeficiencyofinsulinresultsinafailureofnutrients,especiallyglucose,toleavethe bloodandenterthecells.theglucoseinthebloodcreatesadiureticeffect,causingexcessurination orpolyuria.theexcesswaterlosscausesdehydrationandthirstorpolydipsia,asnotedbefore.the waterlossalsocarrieswithitelectrolytelossandsodiumdeficiencyorhyponatremia.lackofglucose to the cells also causes a state of starvation that stimulates the hunger mechanism or polyphagia. Increasedfoodin?takedoesnothelpsincethenutrientscan?notenterthecellsintheabsenceof insulin.theincreasedfoodintakecontributestotheproblemsinceitenhanceshyperglycemia,polyuria, 6

7 anddehydration.thecellularstarvationstatethencausesweightlossinspiteofincreasedfoodintake. Cellularbreakdownalsoresultsinlossofpotassiumfromthecellsandexcretionintheurine,resulting ultimatelyinhypokalemia.thesignsmayincludeaflushedtosallowappearingskin,arapidbythready pulse,andlowbloodpressuredependingonthestateofdehydration).usuallaboratoryfindingsarea phof7.3orless,acarbondioxideleveloflessthan20,apotassiumlevelof3.5orhigherorlowerthe potassium level varies depending on hydration level and a balance of cellular breakdown and excretion), and a sodium level of 135 or lower. The state of consciousness ranges from alert, to obtunded,tofrankcoma,dependingontheph,thelevelofacidosis,andtheelectrolytestatus. Fatbreakdownisanotherresultofinsulindeficiency.FFAsandglycerolareliberatedintothebloodand transportedtotheliverwheretheyareconvertedtoketonebodies.ketonebodiescanbeburnedfor fuelbythecellsbutinthiscaseketonesareproducedfasterthanthecellscanutilizethem.ketones areweakorganicacids.astheyaccumulateinthebloodstream,anacidstateiscreated.buffersystems are mobilized to maintain the normal body ph. The major buffering system in the body is sodium bicarbonate.sincebicarbonateexistsinafixedratiotocarbonicacid,thelattermustbeeliminatedfrom thebodyandbicarbonateisusedtobufferacid.carbonicacidiscarbondioxidedissolvedinwater.the carbondioxideiseliminatedthroughrespiration,causingthedeeplaboredrespiration,acidosisimpairs oxygendissociationfromhb,exacerbatingthegasping. Diagnosisofdiabeticketoacidosis Diagnosis requires demonstration of hyperglycaemia and metabolic acidosis with the presence of ketones.thebio?chemicaldiagnosisofketoacidosisisusuallymadeatthebedsideandconfirmedin thelaboratory.urinalysiswillshowmarkedglycosuriaandketonuria.abloodglucoseteststripusually showsabloodglucoselevelofmorethan22mmol/l TreatmentofDKA Treatment comprises fluid volume expansion initially with 0.9% sodium chloride), correction of hyperglycaemiaandthepresenceofketonesbyinfusionofinsulin),preventionofhypokalaemia,and identification and treatment of any associated infection. Once the patient is better, they should be reviewedbythediabetesteaminordertodiscusshowtoavoidfutureepisodesofdiabeticketoacidosis. 7.3& Hyperosmolar+hyperglycaemic+state++ bloodglucoselevelsmaybetremendouslyelevated mg/dLorso),thepersonmaybealert attheseextremelyhighbloodglucoselevels,but,indka,beunconsciouswithbloodglucoselevelsat 300mg/dLorso.Inmostcases,theindividualwillbeprofoundlydehydrated,butveryinsulinsensitive. Theseindividualsarenotketoticbecausetheyaresecretingsmallamountsofinsulinandtherefore remain extremely sensitive to small dosesofinsulin.controlledadministrationof fluids and drop in bloodglucoselevelsaremandatoryalongwithclosemonitoringofthepotassiumlevels.neurological changesusuallyaremanifestand,frequently,thereisaneedfordailyadministrationofpotassiumfor anumberofdays)andthemonitoringoffluidintakeevenaftertheinitialcrisisisresolved. DiagnosisHHS ThediagnosticfeaturesofHHSarehyperglycaemiaoftenintheregionof55mmol/L,whichisgenerally muchhigherthanfordiabeticketoacidosis),dehydrationandhyperosmolarity.theremaybeamild metabolicacidosisbutwithoutmarkedketoneproduction. TreatmentofHHS Treatment requires fluid replacement to stabilise blood pressure and improve circulation and urine output. Sodium chloride 0.9% is given and monitoring of blood pressure and cardiovascular status undertaken.potassiummaybeaddedifrequired.insulintreatmentisstartedviaintravenousinfusion butisnotaggressive,sincefluidreplacementalsolowersserumglucoselevels. 7

8 Table&6&Pathogenesis&and&clinical&features&of&acute&hyperglycaemia&and&ketoacidosis& 8 Diabeticcomplications 8.1& Macrovascular+disease+ Theriskofmacrovascularcomplications,includingcardiovasculardiseasecoronaryheartdiseaseand stroke)andpvd,is2 4timeshigherforpeoplewithdiabetes. Cardiovascular disease: The most common cause of death in people with type 2 diabetes is cardiovasculardiseasewhichaccountsforanestimated80%ofdeathsinthispatientgroup.therisk ofapersonwithdiabeteshavingamyocardialinfarctionmi)isthesameassomeonewithoutdiabetes having a second myocardial infarction. The risk of cardiovascular disease is increased further if nephropathyispresent. Hypertension:Hypertensionistwiceascommonamongstthediabeticpopulationcomparedtothe generalpopulation.itaffectsover80%ofthosewithtype2diabetes. Peripheralvasculardisease:PVDaffectsthebloodvesselsoutsidetheheart.Inpeoplewithdiabetes, itoftenaffectsthearteriesofthelegsandmaygiverisetointermittentclaudication,acrampingpain experiencedonwalking,duetoreversiblemuscleischaemiasecondarytoatherosclerosis. 8.2& Microvascular+disease++ Microvascularcomplicationsincluderetinopathy,nephropathyandneuropathy. Retinopathy:Diabeticretinopathyistheleadingcauseofblindnessinpeopleundertheageof60in industrialisedcountries.twentyyearsfromtheonsetofdiabetes,over90%ofpeoplewithtype1,and over60%ofpeoplewithtype2,willhavediabeticretinopathy. Nephropathy:Indiabeticrenaldisease,thekidneysbecomeenlargedandtheglomerularfiltrationrate GFR)initiallyincreases.However,ifthenephropathyprogresses,theGFRstartstodecline. The presence of nephropathy is indicated by the detection of microalbuminuria small amounts of albumin present in urine). If higher amounts of albumin are detected, this is termed proteinuria or macroalbuminuria) and signifies more severe renal damage. Microalbuminuria is defined as an albumin:creatinine ratio ACR) greater or equal to 2.5 mg/mmol men) and 3.5 mg/mmol women). Proteinuria may be defined as an albumin: creatinine ratio greater than 30 mg/mmol or albumin concentrationgreaterthan200mg/l.proteinuriamayprogresstoend?stagerenaldiseaseandrequire dialysis. Albumin in the urine increases the risk of cardiovascular disease, with microalbuminuria 8

9 associatedwith2 4timestherisk,proteinuriawithninetimestheriskandend?stagerenaldisease increasingriskby50times. Tightcontrolofbothglycaemiclevelsandbloodpressurereducestheriskofdevelopingnephropathy. Angiotensin?convertingenzymeACE)inhibitorsand/orangiotensinreceptorblockersARBs)arethe treatmentsofchoice. Peripheralneuropathy Peripheralneuropathyistheprogressivelossofperipheralnervefibresresultinginnervedysfunction. whichisparticularlyevidentinthefeetandmayslowlyprogresstoacompletelossoffeelingdiabetic foot). Autonomic neuropathy may affect any part of the sympathetic or parasympathetic nervous systems. The most com? mon manifestation is diabetic impotence. Bladder dysfunction usually manifestsaslossofbladdertonewithalargeincreaseinvolume. 9 Treatment Treatment for people with diabetes includes advice on nutrition, physical activity, weight loss and smokingcessationifappropriate.drugtherapyisprescribedwherenecessary. 9.1& Diet++ Dietary control is the mainstay of treatment for type 2 diabetes and plays an integral part in the managementoftype1. Figure&3&dietary&plan&for&diabetic&patients& 9.2& Insulin+therapy+in+type+1+diabetes++ 9

10 Figure&4&Insulin&doseOresponse&curves.& Untilthe1980s,insulinwasobtainedandpurifiedfromthepancreasofpigsandcows.Humansequence insulinshavesubsequentlybeendevelopedusingrecombinantdnatechnologyandarenowthemost commoninsulinsinuse.thisisdonebyinsertingeithersyntheticgenesfortheinsulinachainandb chain,ortheproinsulingene,oraproinsulin?likepre?cursorintoescherichiacoli. Insulinpreparations Theonsetofaction,peakeffectanddurationofactionaredeterminedbytheinsulintypeandbythe physicalandchemicalformoftheinsulin. FastCactinginsulins. Thefast?actingrecombinantinsulinanaloguesinsulinlispro,insulinaspartandinsulinglulisine)are morerapidlyabsorbedthanthenon?analoguesolubleinsulinsandhaveashorterdurationofaction. Theanaloguesthereforeoffermoreflexibility.Theyaremoreconvenientforsomepatientsastheycan begivenimmediatelybeforeamealratherthanthe30minbeforerecommendedforhumansoluble insulin.anotherbenefitisareducedriskofhypoglycaemiabecauseoftheshorterdurationofaction. IntermediateCactinginsulins. Conventionalintermediate?actinginsulinsareinsoluble,cloudysuspensionsofinsulincomplexedwith eitherprotaminealsoknownasisophaneornphinsulin)orzinclenteinsulin).overtime,insulin dissociatesfromtheprotamine,whichgivesthepreparationitsextendedactivity.theonsetofactionis usually1 2hwiththepeakeffectbeingseenat4 8h.Thereisconsiderableinter?patientvariationin the duration of action, but it usually requires twice?daily administration to adequately cover a 24?h period.protamineinsulinandsolubleinsulindonotinteractwhenmixedtogether.therefore,ready? mixedbiphasic)preparationsareavailablecontainingbothisophaneandsolubleinsulin. LongCactinginsulins. Morerecently,long?actinginsulinanaloguessuchasinsulinglargineandinsulindetemirhavebeen developedusingrecombinantdnatechnology.theybothhaveadurationofactionofabout24hwith amorepredictableaction. Insulindelivery Thesubcutaneousrouteisroutinelyusedformaintenancetherapy,asopposedtotheintravenous routewhichissometimesusedinhospital.insulincanbeinjectedsubcutaneouslyintotheouter 10

11 aspectofthethigh,abdominalwall,buttocksorupperarm.themainadvantagesassociatedwith subcutaneousinjectionareaccessibility,whichallowsmostpatientstoadministertheirowninsulin. administration,althoughthevastmajoritynowusepeninjectiondevices.insulinpensmayeitherbe refillableordisposable.althoughnotinthemselvesimprovingdiabeticcontrol,theyarepopular amongstuserssincetheyarecompactandmoreconvenientastheyremovetheneedtodrawup insulinfromavial Insulin+regimens++ Mealtimeplusbasalregimens Thebestcontrolfortype1diabetesmaybeattainedusingamealtimeplusbasalregimen.Thismimics normalphysiologicalinsulinreleasemorecloselythanotherregimens.amealtimeplusbasalregimen requiresmealtimeinjectionsofinsulinwithafast?actingpreparation,preferablywithananalogue,plus one or two injections of a basal intermediate? or long?acting) insulin. This may require up to five injections a day. The disadvantage of mealtime plus basal regimens is that they require multiple injectionsandrequireregularbloodglucosemonitoringandtheabilityofthepatienttomatchinsulin dosesaccordingtocarbohydrateintake,exerciselevelsandprevailingglucoselevels. TwiceCdailyregimens. The mealtime plus basal regimen may be too hard for some, for example, school?age children, to manage.inthistypeofsituation,atwice?dailyregimenmaybemoresuitable.thesimplestandmost effective twice?daily regimens use premixed insulin, comprising a short? or rapid?acting plus an intermediate?actinginsulin.regularhumaninsulinmixesandanaloguemixesareavailable.theregular humaninsulinmixesshouldbegiven30minbeforebreakfastand30minbeforetheeveningmeal, whereasanaloguemixesmaybegivenimmediatelybeforethesemeals.thelonger?actingcomponent oftheinsulinmixgivenatbreakfasttimemustspanthelunchtimemealandtheeveningdosemust bridgethenighttime. Table&7&Examples&of&insulin&regimens& 11

12 Table&8&Insulin&Stages& Storage+of+insulin+ Insulinformulationsarestableifkeptoutoflight,andtheyarenotsubjecttofreezingorextremesof heat.lossofpotencyof5 10%occursinvialskeptathighambientroomtemperaturesfor2 3 months.insulinshouldthereforebestoredinadomes?ticrefrigeratorexceptforthevials), cartridges)orpensincurrentusewhich,dependingontheindividualpreparation,maybestablefor 4 6weeksseemanufacturers'recommendations).Whenpeninjectordevicesareinuse,theyshould neverbestoredinarefrigeratorastherehavebeenreportsofdevices seizingup whenstoredinthe cold.also,theinjectingofcoldorrefrigeratedinsulinisundesirablebecauseitismorepainfulandthe insulinabsorptionprofileisaltered. 9.3& Management+of+type+2+diabetes++ Intype2diabetes,theprogressivedeclinein?cellfunctionwithtimeandincreasinginsulinresistance meanspeoplewiththisdiseaseshowaprogressivelossofglycaemiccontrolandusuallyrequiretwo orthreedrugstomaintaincontrolbeforeultimatelyrequiringinsulin. Thefactorsusedtoselectaparticulartreatmentincludethepatient'sclinicalcharacteristics,suchas their degree of hyperglycaemia, weight and renal function. In acutely ill people with significant hyperglycaemia,insulintherapymaywellberequired,albeittransientlybecauseacuteillnessleadsto anincreaseinstresshormones,allofwhichareanti?insulin & Biguanides+ Themechanismofactionofbiguanidesisstillnotcompletelyunderstood.However,theprincipalmode ofactionisviapotentiationofinsulinactionatanunknownintracellularlocus,resultingindecreased hepaticglucoseproductionbybothgluconeogenesisandglycogenolysis.metforminalsostimulates tissueuptakeofglucose,particularlyinmuscle,andisthoughttoreducegastro?intestinalabsorptionof 12

13 carbohydrate.theactionofmetformindoesnotinvolvestimulationofpancreaticinsulinsecretionand thereforeitisstillabeneficialagentwhencellfunctionhasdeclined. Anotheradvantageofmetforminoverinsulinstimulators,isthatitdoesnotcausehypoglycaemiaand isnotassociatedwithweightgain.metforminhasashortdurationofaction,withahalf?lifeofbetween 1.3and4.5h,anddoesnotbindtoserumproteins.Itisnotmetabolisedandistotallyrenallyeliminated. Adverseeffects:Themostcommonadverseeffectsofmetformin,affectingaboutathirdofpatients, resultfromgastro?intestinaldisturbancesincludinganorexia,nausea,abdominaldiscomfortand diarrhoea.canbeminimisedbystartingwithalowdose,increasingthedoseslowlyandadministering thedrugwithorafterfood.asuggestedregimenistostartwith500mgdailyfor1week,then500mg twicedailyfor1week,increasingthedosageatweeklyintervalsuntilthedesiredglycaemicresponse isachievedorintoleranceoccurs.themaximumlicenseddoseis3g/day.metforminshouldnotbe prescribedforpatientswhohaverenalimpairmentandinsevereliverdisease,uncontrolledcardiac failureorseverepulmonaryinsufficiency Sulphonylureas++ Modeofaction:Themajoractionofthisclassofdrugreliesontheabilityofthepancreastosecrete insulinandhencerequiresfunctioning?cellstoexertabeneficialeffect.sulphonylureaslowerblood sugarbyincreasingpancreatic?cellsensitivitytoglucose,allowingmoreinsulintobereleasedfrom storagegranulesforagivenglucoseload.sulphonylureastherapyisalsoassociatedwithincreased tissuesensitivitytoinsulin,resultinginimprovedinsulinaction.studiesalsosuggestthat sulphonylureasmaypromoteanincreasedsystemicbioavailabilityofinsulinduetoreducedhepatic extractionoftheinsulinsecretedfromthepancreas. Adverseeffects:Thefrequencyofadverseeffectsfromsulphonylureasislow.Theyareusuallymild andreversibleondrugwithdrawal.themostcommonadverseeffectishypoglycaemia,whichmaybe profoundandlonglasting.hypoglycaemiaduetosulphonylureasisoftenmisdiagnosed,particularlyin theelderly.themajorriskfactorsforthedevelopmentofhypoglycaemiaincludeuseofalong?acting agent,increasingage,renalorhepaticdysfunctionandinadequatecarbohydrateintake.themajor sideeffectis,how?ever,weightgain.otheradverseeffectsarerare\blooddyscrasias,rashesand hyponatraemiaduetoitseffectonincreasingrenalsensitivitytoantidiuretichormoneadh). Sulphonylureadosage:Treatmentshouldstartwithalowdoseandbeincreasedifnecessary approximatelyevery2weeks.formanyagents,themaximumeffectisseenifthedoseistakenhalf anhourbeforeameal,ratherthanwithorafterfood.thenumberofdailydosesrequiredwilldepend ontheagentusedandthetotaldailydose. Druginteractions:Ingestionofalcoholcancausehypoglycaemiainitselfandcanalsoprolongthe hypoglycaemiceffectofsulphonylureas Meglitinides++ Themeglitinidesareinsulin?releasingagentsalsocalled post?prandialglucoseregulators.theyare characterisedbyamorerapidonsetandshorterdurationofactionthansulphonylureas.theirsiteof actionispharmacologicallydistinctfromthatofthesulphonylureas.repaglinide,abenzoicacid derivative,wasthefirstmemberoftheclass.nateglinidewasintroducedlaterandisaderivativeof theaminoacidd?phenylalanine.nateglinideisonlylicensedforcombinationtherapywithmetformin whenmetforminaloneisinadequate. Modeofaction:Likethesulphonylureas,themeglitinidesstimulatefirst?phaseinsulinsecretionby inhibitingatp?sensitivepotassiumchannelsinthemembraneofthepancreatic?cells.thiscauses depolarisation and gating of the calcium channels which are voltage sensitive), increasing the intracellularconcentrationofcalciumandstimulatinginsulinrelease.thereleaseofinsulinonlyoccurs inthepresenceofglucose.asglucoselevelsdrop,lessinsulinissecreted.conversely,ifcarbohydrates areconsumedandglucoselevelsrise,insulinsecretionisenhanced.themeglitinidesshouldbetaken immediately before main meals, although the time can vary up to 30 min before a meal. The 13

14 pharmacokineticprofileofmeglitinidesofferssomeadvantagesinpatientswithpoorrenalfunctionor irregulareatinghabits. Adverseeffects:hypoglycaemia,visualdisturbances,abdominalpain,diarrhoea,constipation, nauseaandvomiting. Dosage:Therecommendedstartingdoseforrepaglinideis500μgbeforeorwitheachmeal,increasing asnecessarydependingonbloodglucosemeasurements)every1 2weekstoamaximumsingledose of4mgandamaximumdailydoseof16mg.whenpatientsaretransferredfromothertherapies,the recommendedstartingdoseis1mgpreprandially.therecommendedstartingdoseofnateglinideis60 mgthreetimesadaybeforemeals,whichmaybesubsequentlyincreasedto120mgthreetimesaday. Themaximumsingledoseis180mg,whichmaybegivenwith thethreemainmealsoftheday. Druginteractions:DrugswhichinduceorinhibitthecytochromeP450enzymesCYP2C8andCYP3A4 interactwithrepaglinide.examplesofdrugswhichenhanceorprolongthehypoglycaemiceffectinclude gemfibrozil, clarithromycin, ketoconazole, itraconazole, trimethoprim, other hypoglycaemic drugs, monoamineoxidaseinhibitors,non?selective?blockers,aceinhibitors,salicylates,nsaids,octreotide, alcoholandanabolicsteroids.drugswhichinducecytochromep450enzymesmayalsointeract,for example,rifampicinandphenytoin,andmaydecreaserepaglinideserumlevels Thiazolidinediones+ Mode of action: The glitazones act as agonists of the nuclear peroxisome proliferator?activated receptor?" PPAR?" ).PPAR?" ismostlyexpressedinadiposetissuebutisalsofoundinpancreatic? cells, vascular endothelium and macrophages. It is also expressed liver and heart. The thiazolidinedioneslowerfastingandpost?prandialglucoselevelsinadditiontoloweringfreefattyacid andinsulinconcentrations.theyenhanceinsulinsensitivityandpromoteglucoseuptakeandutilisation in peripheral tissues. They also suppress gluconeogenesis in the liver and, by increasing insulin sensitivityinadiposetissue,suppressfreefattyacidconcentrations.inaddition,patientswithigthave shown increased insulin secretory responses. However, they do not have a direct effect on insulin secretion. Adverse effects: Pioglitazone has been associated with weight gain and oedema, particularly in patientswithhypertensionandcongestivecardiacfailure.sincethethiazolidinedionescanleadtoa worseningofheartfailurethatmaybefatal,pioglitazoneshouldnotbeusedinpatientswithaprevious historyoforpre?existingheartfailure.combinationtherapywithinsulinandthiazolidinedioneshasbeen foundtoresultinahigherincidenceofoedema.thereisalsoanincreasedriskofbonefracturewith pioglitazone,anditshouldbeusedwithcautioninpost?menopausalwomen. Dosage:Pioglitazoneisstartedatadoseof15mgor30mgandmaybeincreasedto45mgonce daily. In combination with metformin or a sulphonylurea, the current dose can be continued. Administrationofpioglitazonemaybeeitherwithorwithoutfood. Druginteractions:PioglitazoneismetabolisedbycytochromeP450CYP3A4.Therefore,drugswhich induceorinhibitthisenzymeinteractwithpioglitazone.ketoconazole,itraconazole,erythromycinand fluconazoleincreaseserumconcentrations,whilerifampicinandphenytoindecreaseserumlevelsof pioglitazone. Roleofthiazolidinediones:Thiazolidinedionesimproveglycaemiccontrolinpatients,especiallyin thosewithinsulinresistance,byreducinghba1clevelsupto1.5%comparedtosulphonylureaor metforminalone. Glitazonesshouldbeusedasthird?linetherapyafterlifestylemodificationandtheuseofmetforminor asulphonylureaasmonotherapy.however,ifglycaemiccontrolremainspoor,pioglitazonecanbeused eitherwithmetforminiftreatmentwithasulphonylureaisunsuitable,withasulphonylureaiftreatment withmetforminisunsuitable,orwithmetforminandasulphonylureaifinsulinisunsuitable. 14

15 9.3.5 #Hglucosidase+inhibitors++ Acarbosereducescarbohydratedigestionbyinterferingwithgastro?intestinalglucosidaseactivity. Althoughoverallcarbohydrateabsorptionisnotsignificantlyaltered,thepost?prandialhyperglycaemic peaksaremarkedlyreduced.acarboseisminimallyabsorbedinunchangedformfromthegastro? intestinaltract. Adverseeffects:abdominaldiscomfortassociatedwithflatulenceanddiarrhoea.Thesesymptoms usuallyimprovewithcontinuedtreatmentbutcanbeminimisedbystartingwithalowdoseand titratingslowly. Roleofacarbose.Acarboseisatherapeuticoptionintype2patientsinadequatelycontrolledbydiet alone,orbydietandotheroralhypoglycaemicagents.however,thegastro?intestinalsideeffectsdo limittheuseofacarboseinclinicalpractice Dipeptidyl+peptidaseH4+inhibitor+ TheDPP?4inhibitorsareanewclassofdrugsthatworkontheincretinsystem.Theyarealso commonlyreferredtoasthe gliptins. Modeofaction.DPP?4inhibitorsblockthenormalinactivationofincretinsglucagonlikepeptide?1 [GLP?1] and glucose?dependent insulinotropic peptide [GIP]). Incretins play a role in increasing endogenousinsulininresponsetoahighglucoseload,thatis,postprandially.theyalsoreducethe amountofglucoseproducedbytheliverwhenglucoselevelsaresufficientlyhigh.byblockingdpp?4, thesedrugsprolongincretinactivityandinhibitglucagonrelease.thisinturncausesadecreasein bloodglucoseandanincreaseininsulinsecretion. Adverseeffects.AllthreeDPP?4inhibitorshavebeenlinkedtogastro?intestinalsideeffectsand havethepotentialtocausehypoglycaemiawhenprescribedwithotheragentsthatcanproducethis effect. Druginteractions.DPP?4inhibitorshavealowpotentialforinteractionwithothermedicines.However, as both sitagliptin and saxagliptin are metabolised by cytochrome P450 3A4/5 and CYP2C8 for sitagliptin),theyhavethepotentialtointer?actwithpotentinducersorinhibitorsoftheseenzyme. RoleofdipeptidylpeptidaseC4inhibitors.DPP?4inhibitorsarelicensedforuseasdualtherapywith metformin,asulphonylureaorathiazolidinedione.itisrecommendedthatadpp?4inhibitorisusedas third?linetherapytypicallyinthosewhostilldonothaveadequatecontrolorcannottoleratetreatment withmetforminand/orasulphonylurea.dpp?4inhibitorsarealsousefuliffurtherweightgainislikely. However,ifinsulinresistanceisakeyfactor,thentreatingwithathiazolidinedionemaybeabetter choice The+incretin+mimetics+ Theincretinmimetics,asthenamesuggests,mimictheeffectsofincretinsexenatideandliraglutide) are only available as subcutaneously injectable products. Incretin mimetics have both been demonstratedtocauseweightloss,whichisaparticularlybeneficialeffectinmanypatientswithtype2 diabetes. Modeofaction.Theincretinmimeticsbindtoandactivatetheglucagon?likepeptide?1GLP?1) receptor,henceincreasinginsulinsecretion,suppressingglucagonsecretion,increasingsatietyand slowinggastricemptying.alloftheseeffectshelptolowerbloodglucoselevels. Adverseeffects:nausea,andothergastro?intestinaldisturbances.However,oncetherapyhasbeen established,theincidenceofthesesideeffectsdecreases.sincetheincretinmimeticscauseglucose? dependentinsulinrelease,hypoglycaemiaisuncommonandinmostcases,canbeattributedtoother agentstakenconcurrently Druginteractions.Thepotentialfordruginteractionswiththeincretinmimeticsislow.However,as they can cause a delay in gastric emptying, they may influence the absorption of other medicines administeredatthesametime.forthisreason,itisadvisedthatanynarrowtherapeuticindexdrugs takenconcomitantlyaremonitoredcarefully.also,ifotheroralmedicinesarebeingtakenwherethe 15

16 thresholdconcentrationisimportante.g.antibiotics),itisadvisedthattheseshouldbetakenatleast1 hbeforeexenatide. Role of incretin mimetics. It is recommended that exenatide be added to metformin and a sulphonylureaasthird?linetherapyasanalternativetoinsulin,thiazolidinedionesordpp?4inhibitors) for patients who have either a BMI of 35kg/m 2 and have other medical problems associated with increasedbodyweight. Table&9&Pharmacokinetics&of&oral&hypoglycaemic&agents& 10 RoleofclinicalPharmacist:PatientorientedPharmacy Allpatients,andcarers,whereappropriate,willbeencouragedtodevelopapartnershipwith theirclinicianstoenablethemtomanagetheirdiabetesandmaintainahealthylifestyle,often throughsharedcareplans. Structurededucationforpatientswithtype2diabetesisimportantandshouldbeofferedto everypatientand/ortheircareraroundthetimeofdiagnosis.itisconsideredtobeanintegral partofdiabetescare Education will depend upon the individual patient and the availability of local resources. Individualtuitionispreferableintheearlystagesafterdiagnosisandisusuallydeliveredbya diabetesspecialistnurse.theeducationalaspectofcareisagradualandongoingprocess.at alaterstage,groupeducationcanbeeffectiveandmanypatientsappreciateandfindsupport 16

17 inmeetingotherswhohavethesamedisease.manysuchprogrammesaremultidisciplinary andinvolvedoctors,nurses,dieticians,pharmacistsandchiropodists.itisessentialtoinvolve thepatient'sfamilyandcarersintheeducationalprocess. Patientsrequireeducationandinformationaboutmanysubjects,rangingfromgenerallifestyle advicethroughtoknowledgeaboutthemedicinestheyareprescribed. Adviceabouttheuseofover?the?countermedications,diet,footcareproductsanddiabetic foodproductsisfrequentlyrequested. Table&10&common&problems&with&diabetic&therapeutics& 17