DiabetesMellitus

Diabetesmellitus(DM)isagroupofdiseasescharacterizedbyhighlevelsofbloodglucoseresultingfromdefectsininsulinproduction,insulinaction,orboth.Thetermdiabetesmellitusdescribesametabolicdisorderofmultipleaetiologycharacterizedbychronichyperglycaemiawithdisturbancesofcarbohydrate,fatandproteinmetabolismresultingfromdefectsininsulinsecretion,insulinaction,orboth.Theeffectsofdiabetesmellitusincludelong–termdamage,dysfunctionandfailureofvariousorgans.DefinitionDefinitionInsulindeficiencyInsulinresistanceHyperglycemiaCarbohydrateFatProteinLong-termdamagesinvariousorgansType1DiabetesMellitusType2DiabetesMellitusGestationalDiabetesMellitus(GDM)Othertypes:LADA(LatentAutoimmuneDiabetesinAdults)MODY(maturity-onsetdiabetesofyouth)SecondaryDiabetesMellitusTypesofDiabetes

Previouslycalledinsulin-dependentdiabetesmellitus(IDDM)orjuvenile-onsetdiabetes.Type1diabetesdevelopswhenthebody’simmunesystemdestroyspancreaticbetacells,theonlycellsinthebodythatmakethehormoneinsulinthatregulatesbloodglucose.Thisformofdiabetesusuallystrikeschildrenandyoungadults,althoughdiseaseonsetcanoccuratanyage.Type1diabetesmayaccountfor5%to10%ofalldiagnosedcasesofdiabetes.Riskfactorsfortype1diabetesmayincludeautoimmune,genetic,andenvironmentalfactors.Type1diabetesPreviouslycallednon-insulin-dependentdiabetesmellitus(NIDDM)oradult-onsetdiabetes.Type2diabetesmayaccountforabout90%to95%ofalldiagnosedcasesofdiabetes.Itusuallybeginsasinsulinresistance,adisorderinwhichthecellsdonotuseinsulinproperly.Astheneedforinsulinrises,thepancreasgraduallylosesitsabilitytoproduceinsulin.Type2diabetesisassociatedwitholderage,obesity,familyhistoryofdiabetes,historyofgestationaldiabetes,impairedglucosemetabolism,physicalinactivity,andrace/ethnicity.Type2diabetesisincreasinglybeingdiagnosedinchildrenandadolescents.Type2diabetesAformofglucoseintolerancethatisdiagnosedinsomewomenduringpregnancy.GestationaldiabetesoccursmorefrequentlyamongAfricanAmericans,Hispanic/LatinoAmericans,andAmericanIndians.Itisalsomorecommonamongobesewomenandwomenwithafamilyhistoryofdiabetes.Duringpregnancy,gestationaldiabetesrequirestreatmenttonormalizematernalbloodglucoselevelstoavoidcomplicationsintheinfant.Afterpregnancy,5%to10%ofwomenwithgestationaldiabetesarefoundtohavetype2diabetes.Womenwhohavehadgestationaldiabeteshavea20%to50%chanceofdevelopingdiabetesinthenext5-10years.GestationaldiabetesGDMGestationaldiabetesmellitus(GDM):anydegreeofglucoseintolerancewithonsetorfirstrecognitionduringpregnancy.MaygoawayafterthebabyisbornButsomewomenwiththistypeofdiabetesmaybemorelikelytodeveloppermanentdiabetesafterpregnancyCancauseproblemsforthebabyincludingheartandlungproblemsandproblemswiththebaby’ssugarOtherspecifictypesofdiabetesresultfromspecificgeneticconditions(suchasmaturity-onsetdiabetesofyouth),surgery,drugs,malnutrition,infections,andotherillnesses.Suchtypesofdiabetesmayaccountfor1%to5%ofalldiagnosedcasesofdiabetes.OthertypesofDMLatentAutoimmuneDiabetesinAdults(LADA)isaformofautoimmune(type

1diabetes)whichisdiagnosedinindividualswhoareolderthantheusualageofonsetoftype1diabetes.Alternatetermsthathavebeenusedfor"LADA"includeLate-onsetAutoimmuneDiabetesofAdulthood,"SlowOnsetType1"diabetes,andsometimesalso"Type1.5diabetes”.Often,patientswithLADAaremistakenlythoughttohavetype

2diabetes,basedontheirageatthetimeofdiagnosis.LADALADAMODY–MaturityOnsetDiabetesoftheYoungMODYisamonogenicformofdiabeteswithanautosomaldominantmodeofinheritance:Mutationsinanyoneofseveraltranscriptionfactorsorintheenzymeglucokinaseleadtoinsufficientinsulinreleasefrompancreatic?-cells,causingMODY.DifferentsubtypesofMODYareidentifiedbasedonthemutatedgene.MODYMODYMutationMODY1HNF-4aMODY2GlucokinaseMODY3HNF-1aMODY4IPF-1MODY5HNF-1bMODY6NeuroD1MODYGlucokinaseMODYrequiresnotreatment,whiletranscriptionfactorMODY(i.e.Hepatocytenuclearfactor-1alpha)requireslow-dosesulfonylureatherapy.Acromegaly,--GHCushingsyndrome,--CortisolThyrotoxicosis,--T3T4Pheochromocytoma,PHA--CA,catecholamineCancer,--lungcancer

ACTHChronicpancreatitis,--insulininsufficiencyDruginducedhyperglycemia:Beta-blockers-Inhibitinsulinsecretion.Corticosteroids-Causeperipheralinsulinresistanceandgluconeogensis.SecondaryDMHormoneswhichcanincreaseglucoseClinicalPresentationType1DMPolyuriaPolydipsiaPolyphagiaWeightlossWeaknessDryskinKetoacidosisType2DMPatientscanbeasymptomaticPolyuriaPolydipsiaPolyphagiaFatigueWeightlossMostpatientsarediscoveredwhileperformingurineglucosescreeningDiagnosisofDiabetesMellitusLaboratoryTests1.GlucosuriaTodetectglucoseinurine2.KetonuriaTodetectketonbodiesinurine3.FastingbloodglucoseGlucosebloodconcentrationinsamplesobtainedafteratleast8hoursofthelastmeal4.RandomBloodglucoseGlucosebloodconcentrationinsamplesobtainedatanytimeregardlessthetimeofthelastmealLaboratoryTests5.Glucosetolerancetest75gmofglucosearegiventothepatientwith300mlofwaterafteranovernightfastBloodsamplesaredrawn1,2,and3hoursaftertakingtheglucoseThisisamoreaccuratetestforglucoseutilizationifthefastingglucoseisborderline

Plusinsulinreleasetest(IRT)andC-peptidetestbetacellreserveevaluation5.Glucosetolerancetest(cont.)Itisestimatedmorethan50%ofbetacellswerelostattheonsetofdiabetes.LaboratoryTestsDisulfidebondValuesofDiagnosisofDiabetesMellitusValuesofDiagnosisofDiabetesMellitus75gmofglucosearegiventothepatientwith300mlofwaterafteranovernightfast(12h)----24-28wTimeGlucose(mmol/L)0h5.11h10.02h8.5Onetime-pointexceedsnormalrangeGDMGDMGLUCOSETEST6.Glycosylatedhemoglobin(HbA1C)HbA1CisformedbycondensationofglucosewithfreeaminogroupsoftheglobincomponentofhemoglobinNormallyitcomprises4-6%ofthetotalhemoglobin.Increaseintheglucosebloodconcentrationincreasestheglycatedhemoglobinfraction.HbA1Creflectstheglycemicstateduringthepreceding8-12weeks.LaboratoryTests7.SerumFructosamineFormedbyglycosylationofserumprotein(mainlyalbumin)Sinceserumalbuminhasshorterhalflifethanhemoglobin,serumfructosaminereflectstheglycemicstateinthepreceding2weeksNormalis1.5-2.4mmol/Lwhenserumalbuminis5g/dL.LaboratoryTestsLaboratoryTests8.AutoantibodiesInsulinautoantibody(IAA):morefrequentlydetectedinveryyoungchilddiabetesIsletcellantibody(ICA):morefrequentlydetectedinjuvenilediabetesGlutamicaciddecarboxylase(GADA):appearsrelativelylatePrediabetesisatermusedtodistinguishpeoplewhoareatincreasedriskofdevelopingdiabetes.Peoplewithprediabeteshaveimpairedfastingglucose(IFG)orimpairedglucosetolerance(IGT).SomepeoplemayhavebothIFGandIGT.IFGisaconditioninwhichthefastingbloodsugarleveliselevated(6.1-6.9mmol/L)afteranovernightfastbutisnothighenoughtobeclassifiedasdiabetes.IGTisaconditioninwhichthebloodsugarleveliselevated(7.8-11.1mmol/L)aftera2-houroralglucosetolerancetest,butisnothighenoughtobeclassifiedasdiabetes.Prediabetes:Impairedglucosetoleranceandimpairedfastingglucose

DiagnosticCriteria

CharacteristicsType1Type2%ofdiabeticpop5-10%90%AgeofonsetUsually<30yr+someadultsUsually>40+someobesechildrenPancreaticfunctionUsuallynoneInsulinislow,normalorhighPathogenesisAutoimmuneprocessAuto-antibodiespositive(GADA+)Defectininsulinsecretion,tissueresistancetoinsulinAuto-antibodiesnegativeFamilyhistoryGenerallynotstrongStrongObesityUncommonCommonHistoryofketoacidosisOftenpresentRareexceptinstressClinicalpresentationmoderatetoseveresymptoms:3Ps,fatigue,wtlossandketoacidosisMildsymptoms:Polyuriaandfatigue.DiagnosedonroutinephysicalexaminationTreatmentInsulin,DietExerciseDiet,ExerciseOralantidiabetics,InsulinManagementofDiabetesMellitusThemajorcomponentsofthetreatmentofdiabetesare:ManagementofDMADiet,Exercise,andSelfcareBOralhypoglycaemictherapyCInsulinTherapy

GlycemicgoalsDietisabasicpartofmanagementineverycase.Treatmentcannotbeeffectiveunlessadequateattentionisgiventoensuringappropriatenutrition.Dietarytreatmentshouldaimat:ensuringweightcontrolprovidingnutritionalrequirementsallowinggoodglycaemiccontrolwithbloodglucoselevelsasclosetonormalaspossiblecorrectinganyassociatedbloodlipidabnormalitiesA.1DietThefollowingprinciplesarerecommendedasdietaryguidelinesforpeoplewithdiabetes:Dietaryfatshouldprovide25-35%oftotalintakeofcaloriesbutsaturatedfatintakeshouldnotexceed10%oftotalenergy.Cholesterolconsumptionshouldberestrictedandlimitedto300mgorlessdaily.Proteinintakecanrangebetween10-15%totalenergy(0.8-1g/kgofdesirablebodyweight).Requirementsincreaseforchildrenandduringpregnancy.Proteinshouldbederivedfrombothanimalandvegetablesources.Carbohydratesprovide50-60%oftotalcaloriccontentofthediet.Carbohydratesshouldbecomplexandhighinfibre.Excessivesaltintakeistobeavoided.Itshouldbeparticularlyrestrictedinpeoplewithhypertensionandthosewithnephropathy.A.1Diet(cont.)Physicalactivitypromotesweightreductionandimprovesinsulinsensitivity,thusloweringbloodglucoselevels.Togetherwithdietarytreatment,aprogrammeofregularphysicalactivityandexerciseshouldbeconsideredforeachperson.Suchaprogrammemustbetailoredtotheindividual’shealthstatusandfitness.Peopleshould,however,beeducatedaboutthepotentialriskofhypoglycaemiaandhowtoavoidit.A.2ExercisePatientsshouldbeeducatedtopracticeself-care.Thisallowsthepatienttoassumeresponsibilityandcontrolofhis/herowndiabetesmanagement.Self-careshouldinclude:BloodglucosemonitoringBodyweightmonitoringFoot-carePersonalhygieneHealthylifestyle/dietorphysicalactivityIdentifytargetsforcontrolStoppingsmokingA.3Self-Care

Therearecurrentlysixclassesoforalanti-diabeticagents:i.Biguanidesii.InsulinSecretagogues–SulphonylureasandGlinidesiii.α-glucosidaseinhibitorsiv.Thiazolidinediones(TZDs)v.DPP4(dipeptidylpeptidase4)inhibitorsvi.SGLT(sodium-glucosecotransporter-2)inhibitorsB.OralAnti-DiabeticDrugs(OADs)OralHypoglycaemicMedicationsMajorTherapeuticTargetsinT2DMGlucose

absorptionHepaticglucose

overproductionInsulin

resistancePancreasMuscleandfatLiverMetforminThiazolidinedionesGLP-1agonistsDPP-4inhibitorsSulfonylureasMeglitinidesGLP-1agonistsDPP-4inhibitorsThiazolidinedionesMetforminAlpha-glucosidaseinhibitorsGLP-1agonistsGutGlucose

reabsorptionKidneyBeta-cell

dysfunctionGlucoselevelSGLT-2inhibitorsAbbreviations:DPP-4,dipeptidylpeptidase-4;GLP-1,glucagon-likepeptide-1;T2DM,type2diabetesmellitus.41B1.SulfonylureasPharmacologicaleffectStimulatethepancreaticsecretionofinsulinSulfonylureasbindtoandclose

ATP-sensitiveK+(KATP)channelsonthecellmembraneofpancreatic

betacells,whichdepolarizesthecellbypreventingpotassiumfromexiting.This

depolarization

opensvoltage-gated

Ca2+

channels.Theriseinintracellularcalciumleadstoincreasedfusionof

insulin

granulaewiththecellmembrane,andthereforeincreasedsecretionof(pro)insulin.43B1.Sulfonylureas(Cont’d)ClassificationFirstgeneratione.g.tolbutamide,chlorpropamide,andacetohexamideLowerpotency,morepotentialfordruginteractionsandsideeffectsSecond/Thirdgeneratione.g.glimepiride,glipizide,andglyburidehigherpotency,lesspotentialfordruginteractionsandsideeffectsAllsulfonylureadrugsareequallyeffectiveinreducingthebloodglucosewhengiveninequipotentdoses.MajorPharmacokineticPropertiesofSulfonylureasEqv.Dose(mg)Duration(h)ActivemetabolitesFirstGenerationTolbutamide1000-150012-24Yes(p-OHderivative)Chlorpropamide250-37524-60Yes(2’-OHand3’OHgroups)Tolazamide250-37512-24No(4-COOHderivative)Secondgeneration

Glipizide1010-24No(cleavageofpyrazinering)

Glyburide(glibenclamide)

Thirdgeneration516-24Some(trans+cis4’-OHgroups)

Glimepiride1-224Yes(-OHonCH3ofR’group)B1.Sulfonylureas(Cont’d)AdverseeffectsHypoglycemiaWeightgainHbA1c:1.5–1.7%reduction.FPG:50–70mg/dLreduction.PPG:92mg/dLreduction.EfficacyB2.GlinidesPharmacologicaleffectStimulationofthepancreaticsecretionofinsulinShouldbegivenbeforemealorwiththefirstbiteofeachmeal.Ifyouskipamealdon’ttakethedose!RepaglinideNateglinideShort-actingSecretogoguesTheybindtoan

ATP-dependent

K+

(KATP)channelonthecellmembraneofpancreatic

betacells

inasimilarmannerto

sulfonylureas

buthaveaweakerbindingaffinityandfasterdissociationfromtheSUR1bindingsite.Glinides48Incidenceofhypoglycemiaisverylowabout0.3%AdverseeffectDrugInteractionsInducersorinhibitorsofCYP3A4affecttheactionofrepaglinideNateglinideisaninhibitorofCYP2C9B2.GlinidesB3.BiguanidesPharmacologicaleffectReduceshepaticglucoseproductionIncreasesperipheralglucoseutilizationMetforminAdverseeffectsNausea,vomiting,diarrhea,andanorexiaAsaprecautionmetforminshouldnotbeusedinpatientswithrenalinsufficiency,CHF,conditionsthatleadtohypoxiaB4.Glitazones(PPARgAgonists)PPARgAgonists:Peroxisomeproliferator-activatedreceptorggonistsRosiglitazone-PioglitazoneReducesinsulinresistanceintheperiphery(Sensitizemuscleandfattotheactionofinsulin)andpossiblyintheliverTheonsetofactionisslowtaking2-3monthstoseethefulleffectEdemaandweightgainarethemostcommonsideeffects.(nohepatotoxicity)PharmacologicaleffectPPARrAgonistB5.a-GlucosidaseInhibitorsPharmacologicaleffectPreventthebreakdownofsucroseandcomplexcarbohydratesTheneteffectistoreducepostprandialbloodglucoseriseTheeffectislimitedtotheluminalsideoftheintestinewithlimitedsystemicabsorption.Majorityeliminatedinthefeces.Postprandialglucoseconcisreduced.FPGrelativelyunchanged.AveragereductioninHbA1c:0.3-1.0%-Acarbose-Voglibose-MiglitolAtinsulininitiation,theaveragepatienthad:5yearswithHbA1c>8%10yearswithHbA1c>7%TraditionalApproachestoTherapyResult

inProlongedExposuretoElevatedGlucoseBrownJB,etal.DiabetesCare.2004;27(7):1535-1540.SulfonylureaorMetforminMonotherapyCombination

TherapyDiet/ExerciseMeanHbA1cat

LastVisit(%)Years Diagnosis 2 3 4 5 6 7 8 9 108.6%678910Insulin9.6%ADAGoal<7%AACEGoal<6.5%9.0%Inelderlynon-obesepatients,shortactinginsulinsecretagoguescanbestartedbutlongactingSulphonylureasaretobeavoided.Renalfunctionshouldbemonitored.Oralanti-diabeticagentsarenotrecommendedfordiabetesinpregnancyOralanti-diabeticagentsareusuallynotthefirstlinetherapyindiabetesdiagnosedduringstress,suchasinfections.InsulintherapyisrecommendedforboththeaboveTargetsforcontrolareapplicableforallagegroups.However,inpatientswithco-morbidities,targetsareindividualizedWhenindicated,startwithaminimaldoseoforalanti-diabeticagent,whilereemphasizingdietandphysicalactivity.Anappropriatedurationoftime(2-16weeksdependingonagentsused)betweenincrementsshouldbegiventoallowachievementofsteadystatebloodglucosecontrolGeneralGuidelinesforUseofOralAnti-DiabeticAgentinDiabetes

Asfirstlinetherapy:Obesetype2patients,consideruseofmetformin,acarboseorTZD.Non-obesetype2patients,considertheuseofmetforminorinsulinsecretagoguesMetforministhedrugofchoiceinoverweight/obesepatients.TZDsandacarboseareacceptablealternativesinthosewhoareintoleranttometformin.Ifmonotherapyfails,acombinationofTZDs,acarboseandmetforminisrecommended.Iftargetsarestillnotachieved,insulinsecretagoguesmaybeaddedOralAgentMonotherapyCombinationoralagentsisindicatedin:NewlydiagnosedsymptomaticpatientswithHbA1c>7.5Patientswhoarenotreachingtargetsafter3monthsonmonotherapyCombinationOralAgents

C.InsulinTherapyThenumberofunits/ml e.g.U-100,U-20,U-10StrengthSourceSwine:Differsbyonea.a.OxHuman(recombinantDNAtechnology)C.InsulinTherapy-insulintype

C.Insulin(Cont’d)-insulintypeChangingthepropertiesofinsulinpreparationcanaltertheonsetanddurationofactionLispro:(Monomeric)absorbedtothecirculationveryrapidlyAspart: (Mono-anddimeric)absorbedtothecirculationveryrapidlyOnsetanddurationofeffectC.Insulin(Cont’d))-insulintypeLenteinsulin:Amorphousprecipitateofinsulinandzincandinsolublecrystalsofinsulinandzinc.ReleasesinsulinslowlytothecirculationNPH:R-insulin+Protaminezincinsulin.ReleasesinsulinslowlytothesystemiccirculationInsulinglargine:Preparedbymodificationoftheinsulinstructure.PrecipitateafterS.C.injectiontoformmicrocrystalsthatslowlyreleaseinsulintothesystemiccirculation(N.B.cannotbemixedwithotherinsulins)OnsetanddurationofeffectC.Insulin(Cont’d))-insulintypeRapid-actinginsuline.g.InsulinlisproandinsulinaspartShort-actinginsuline.g.Regularinsulin(RI),Novolin-R,Humulin-RIntermediate-actinginsuline.g.NPHandLenteinsulinLong-actinginsuline.g.InsulinGlargineMixtureofinsulincanprovideglycemiccontroloverextendedperiodoftimee.g.Novomix30(70%NPH+30%NovorapidAspart)OnsetanddurationofeffectC.Insulin(Cont’d)HypoglycemiaTreatment:

PatientsshouldbeawareofsymptomsofhypoglycemiaOraladministrationof10-15gmglucoseIVglucoseinpatientswithlostconsciousness1gmglucagonIMifIVaccessisnotavailableSkinrashatinjectionsiteTreatment:

UsemorepurifiedinsulinpreparationLipodystrophies(increaseinfatmass)atinjectionsiteTreatment:

rotatethesiteofinjectionAdverseeffectsC.Insulin(Cont’d)MethodsofInsulinAdministrationInsulinsyringesandneedlesPen-sizedinjectorsInsulinPumpsRINovoMix30NovoRapidShort-termuse:Acuteillness,surgery,stressandemergenciesPregnancyBreast-feedinginmarkedhyperglycaemiaSeveremetabolicdecompensation(diabeticketoacidosis,hyperosmolarnonketoticcoma,lacticacidosis,severehypertriglyceridaemia)C.Insulin-Therapy-Howtouseinsulin

Long-termuse:IftargetshavenotbeenreachedafteroptimaldoseofOADcombinationtherapy,considerchangetoinsulintherapy.C.Insulin-Therapy-Howtouseinsulin

Howtouseinsulin:1Regimen2DoseNormalinsulinsecretionduringadayBreakfastLunchSupperInsulinConcentrationTimeofday-Constantbackgroundlevel(basal)-SpikesofinsulinsecretionaftereatingTheinsulinregimenhastomimicthephysiologicalsecretionofinsulinThemajorityofpatientswillrequiremorethanonedailyinjectionifgoodglycaemiccontrolistobeachieved.However,aonce-dailyinjectionofanintermediateactingpreparationmaybeeffectivelyusedinsomepatients.Twice-dailymixturesofshort-andintermediate-actinginsulinisacommonlyusedregimen.Third-dailymixturescanbechosewhentwice-injectionregimencannotgettheglucosetarget.Threeinjectionsofregularorrapidactinginsulinbeforeeachmeal+longactinginsulinatbedtime(4injections).Insomecases,amixtureofshort-andintermediate-actinginsulinmaybegiveninthemorning.Furtherdosesofshort-actinginsulinaregivenbeforelunchandtheeveningmealandaneveningdoseofintermediate-actinginsulinisgivenatbedtime.InsulinPumpThechoiceoftheregimenwilldependonthepatient

C.Insulin-Therapy--Insulinregimens

C.Insulin-Therapy--InsulinregimensBreakfastLunchSupperInsulinConcentrationGlarginecontrolbaseglucoselevelAcarbosecontrolmealtimeglucoselevelGlargineAcarboseAcarboseAcarboseCombinationofinsulin+oralanti-diabeticagentshasbeenshowntoimproveglycaemiccontrolinthosenotachievingtargetdespitemaximalcombinationoralanti-diabeticagents.Combininginsulinandthefollowingoralanti-diabeticagentshasbeenshowntobeeffectiveinpeoplewithtype2diabetes:Biguanide(metformin)Insulinsecretagogues(sulphonylureas)α-glucosidaseinhibitor(acarbose)InsulindosecanbeincreaseduntiltargetFPGisachieved.CombinationOralAgentsandInsulin

C.Insulin-Therapy--InsulinregimensBreakfastLunchSupperInsulinConcentrationNovoMix30+AcarboseNovoRapid(30%Aspart)controlbaseglucoselevelNovoLinNPH(ProtamineInsulinAspart70%)controlmealtimeglucoselevelNovoMix30NovoMix30NovoMix30AcarboseC.Insulin-Therapy--InsulinregimensBreakfastLunchSupperInsulinConcentrationGlarginecontrolbaseglucoselevelNovoRapidcontrolmealtimeglucoselevelNovoRapidGlargineNovoRapidNovoRapidC.Insulin-Therapy--InsulinregimensBreakfastLunchSupperInsulinConcentrationIusulinpumpBasecontrolbaseglucoselevelBoluscontrolmealtimeglucoselevelBolusBaseBolusBolusInsulinPumpTheinsulinpumpdeliversasingletypeofrapid-actinginsulinintwoways:abolusdosethatispumpedtocoverfoodeatenortocorrectahighbloodglucoselevel.abasaldosethatispumpedcontinuouslyatanadjustablebasalratetodeliverinsulinneededbetweenmealsandatnight.CSII:ContinuoussubcutaneousinsulininfusionHowmuchinsulin?1injection+OADAgoodstartingdoseis0.2-0.4U/kg/dayExample:Fora50kgpatientThetotaldose=0.2X50=10U/dayGlargine10uihbeforesleep

C.Insulin-Therapy--InsulindoseHowmuchinsulin?2injections3injectionsAgoodstartingdoseis0.4-0.6U/kg/dayThetotaldoseshouldbedividedto:

-3/6pre-breakfast -1/6pre-lunch -2/6pre-supper

C.Insulin-Therapy--Insulindose

-2/3pre-breakfast-1/3pre-supper

Example:Fora50kgpatientThetotaldose=0.6X50=30U/day2injections:20upre-breakfast(Novomix3020uih)10upre-supper(Novomix3010uih)3injections:15upre-breakfast(Novomix3015uih)5upre-lunch(Novomix3010uih)10upre-supper(Novomix3010uih)

C.Insulin-Therapy--InsulindoseHowmuchinsulin?4injections,5injections,insulinpumpAgoodstartingdoseis0.4-0.6U/kg/dayThetotaldoseshouldbedividedto:50%forbasalinsulin50%forprandialinsulinTheprandialdoseisdividedto

- 1/3pre-breakfast -1/3pre-lunch -1/3pre-supper

C.Insulin-Therapy--InsulindoseExample:Fora50kgpatientThetotaldose=0.6X50=30U/day15Uforbasalinsulin(50%ofdose)Administeredinone(Glargine)ortwodoses(NPH)orbaserate(insulinpump,0.6u/h)15Uforprandialinsulin(50%ofdose)The15Uaredividedto:

- 5Upre-breakfast(Aspart5uihorinsulinpumpbolus5u) -5Upre-lunch(Aspartorinsulinpumpbolus5u) -5Upre-supper(Aspartorinsulinpumpbolus5u)

C.Insulin-Therapy--InsulindoseLimitationsofAgentsforT2DMLimitationAgentHypoglycemiaSecretagogues,insulinWeightgainSecretagogues,glitazones,insulinEdemaGlitazones,insulinGIsideeffectsMetformin,alpha-glucosidaseinhibitorsLacticacidosis(rare)MetforminSafetyissuesinelderly,renal-impaired,orCHFpatientsGlitazones,metformin,sulfonylureasPoorresponseratesAlloralmedicationsLackofdurableeffectAlloralmonotherapyexceptglitazonesAbbreviations:CHF,congestiveheartfailure;GI,gastrointestinal.ComplicationsofdiabetesmellitusComplicationsofdiabetesmellitusAcutecomplications:KetoacidosisThehyperglycemichyperosmolarnonketoticsyndromeHypoglycemiaChroniccomplications:DisordersofthemicrocirculationNeuropathiesNephropathiesRetinopathiesMacrovascularcomplicationsFootulcersThelong–termeffectsofdiabetesmellitusincludeprogressivedevelopmentofthespecificcomplicationsofretinopathywithpotentialblindness,nephropathythatmayleadtorenalfailure,and/orneuropathywithriskoffootulcers,amputation,Charcotjoints,andfeaturesofautonomicdysfunction,includingsexualdysfunction.Peoplewithdiabetesareatincreasedriskofcardiovascular,peripheralvascularandcerebrovasculardisease.Chroniccomplications1.PeripheralneuropathiesTwotypesofpathologicchangeshavebeenobservedinconnectionwithdiabeticperipheralneuropathies.Thefirstisathickeningofthewallsofthenutrientvesselsthatsupplythenerve,leadingtotheassumptionthatvesselischemiaplaysamajorroleinthedevelopmentoftheseneuralchanges.ThesecondfindingisasegmentaldemyelinizationprocessthataffectstheSchwanncell.Thisdemyelinizationprocessisaccompaniedbyaslowingofnerveconduction.Theclinicalmanifestationsofthediabeticperipheralneuropathiesvarywiththelocationofthelesion.ClassificationofdiabeticperipheralneuropathiesSomatic:Polyneuropathies(bilateralsensory)Paresthesias,includingnumbnessandtinglingImpairedpain,temperature,lighttouch,two-pointdiscrimination,andvibratorysensationDecreasedankleandknee-jerkreflexesMononeuropathiesInvolvementofamixednervetrunkthatincludeslossofsensation,pain,andmotorweakness.AmyotrophyAssociatedwithmuscleweakness,wasting,andseverepainofmusclesinthepelvicgirdleandthigh.Autonomic:ImpairedvasomotorfunctionPosturalhypotensionImpairedgastrointestinalfunctionGastricatonyDiarrhea,