1

DIABETESMELLITUS23

DiabetesMellitus-----asyndromewithdisorderedmetabolismandinappropriatehyperglycemiaduetoeitheradeficiencyofinsulinsecretionortoinsulinresistanceandinadequateinsulinsecretiontocompensate.4DiabetesnaturalhistoryClinicalDiabetesVolume18,Number2,2000-15-10-505101520253035030025020015010050PBGFBGBGNGTIGT/IFGNot-DiagnosisDMDMMacroCompl.MicroCompl.5ETIOLOGY

Octetteneurotransmitterdysfunction62型糖尿病---進(jìn)展性疾病-30-20-100102030餐后血糖空腹血糖胰島素抵抗胰島素分泌

血漿葡萄糖126mg/dl

相對(duì)細(xì)胞功能7Classification

81.

Type1DiabetesMellitus

Immune-mediatedtype1diabetesmellitus

Idiopathictype1diabetesmellitus2.

Type2DiabetesMellitus3.GestationaldiabetesMellitus94.

OtherSpecificTypesofDiabetes

(1)

HereditarydefectofBcellfunction:

Maturity-onsetdiabetesoftheyoung(MODY)DiabetesassociatedwithamutationofmitochondrialDNA(2)Hereditarydefectofinsulinaction:

lipoatrophiadiabetesmellitus

10(3)Endocrinedisease：

Cushing’ssyndrome,Hyperthyroidism(4)Diseaseofthepancreas:

pancreatitis,Surgery,trauma,cancer11(5)Diabetesduetodrug:

glucocorticoid,thyroidhormones,thiazidediuretic(6)Infection:

congenitalrubella,cytomegalovirus12(7)Otherinheriteddisease:

Turnersyndrome(8)uncommonimmune-mediateddiabetes:

insulinautoimmunesyndrome,acanthosisnigricans13Pathogenesis14Type1DiabetesMellitus

Type1diabetesiscausedbyauto-immunityagainsttheB-cellsofthepancreas,whicheventuallydestroysthemcompletelyandcausesabsoluteinsulindeficiency.15

TherateofpancreaticBcelldestructionisquitevariable,beingrapidinsomeindividualsandslowinothers.16

predisposinggenes(HLA-DQ)↓virusautoimmune(B-cell)↓antibodies(ICA,IAA,GAD)↓Bcellfunctiondamaged↓hyperglycemia17Type2diabetesmellitus

Theoriginoftype2diabetesismultifactorial,includinggeneticandenvironmentalfactors.Howthesefactorsrelatetotheoriginofmetabolicabnormalitiesobservedwithtype2diabetes,suchasinsulinresistanceanddecreasedinsulinsecretion,iscurrentlyunclear.18191.GeneticandEnvironmentalfactorPolygenicvariationareassociatewithtype2diabetes.Environmentalfactors

undoubtedlyinteractwithgeneticsusceptibility,suchasaging,obesity,diet,andlifestyle.20Riskfactors212.InsulinresistanceandBcellfunctiondefection3.Glucotoxicityandlipotoxicity4.Clinicaldiabetesmellitus22Clinicalmanifestation231.SymptomsandSignsWeightlossPolyphagiaPolyuriaPolydipsia

24

Type1diabetesoccurinthethinandyoung.Itoftenpresentswithcharacteristicfeatures.Anabsolutedeficiencyofinsulinresultsinaccumulationofcirculatingglucoseandfattyacids,withconsequenthyperketonemia.25

LADA(Latentautoimmunediabetesinadults)

oftenoccurinadultsespeciallythenonobesewithabsolutedeficiencyofinsulinandinsulinautoimmuneantibodyisalwayspositive.26

Type2diabetestendtooccurintheoverweightandelderly.Itisoftenasymptomaticanddetectedbyhealthexamination.Occasionally,type2patientsmaypresentwithevidenceofchroniccomplicationsbecauseofoccultdiseasepresentforsometimepriortodiagnosis.27-------------------------------------------------------------------------------Type1DMType2DM--------------------------------------------------------------------------------AgeofonsetYoungadultWeightLeanObeseOnsetMoreabruptMaybeveryinsidiousSymptomcharacteristicfeaturesasymptomaticInsulinabsolutedeficiencyrelative/resistanceTreatmentinsulinoraldrug

Ketosispronefrequentlyrarely--------------------------------------------------------------------------282.ComplicationofdiabetesA.Chroniccomplication(1)largevesseldisease

Atherosclerosisiswides-preadandearlyinonset.Itleadstocoronaryheartdisease,hypertensionandstroke29(2)SmallvesseldiseaseDiabeticmicroangiopathyisassociatedwithhomogeneousthickeningofthevascularbasementmembraneandendothelialproliferation.30

Diabeticretinopathy

backgroundretinopathy

microaneurysmshemorrhagesexudates

31Proliferativeretinopathynewlyformedvesselvitreoushemorrhage,scarringretinaldetachment,blindness3233newlyformedvesselvitreoushemorrhage34microaneurysmshemorrhagesexudates35

Diabeticcataractsandglaucomaarethecommonocularcomplication,whichresultinblindnesstoo.36DiabeticNephropathy

Intype1diabetes,upto40%ofpatientsdevelopendstagerenaldisease,comparedwithlessthan20%ofpatientswithtype2diabetes.37

Althoughdiffuseglomerularsclerosisoccursinover70%ofdiabetes,nodularglomerularsclerosisispathognomonicofdiabetes.Diabeticnephropathyisinitiallymanifestedbyproteinuria,subsequently,kidneyfunctiondeclines.38(1)Thefirstperiod

enlargekidneys,hyperfiltration,normoalbuminuria

39(2)Thesecondperiod

thickeningofglomerularbasementmembrane

microalbuminuriaperiodintermittent40(3)Thethirdperiodmicroalbuminuriaperiodpersistent(UAE20-200ug/min)41(4)Thefourthperiod

increastedmicroalbuminuria(UAE>200ug/min)patientsmaybepresentwithedema,hypertension,andkidneyfunctiondecline42(5)Thefifthperiod

uremicperiod,creatinineandureanitrogenaccumulateintheblood.4344Diabeticneuropathy

45Peripheralneuropathy

thecommonmanifestationissymmetricalsensorylossinthedistallowerlimbs.Patientspresentwithnumbness,burning,lightningpainthatisworseatnight.46

Singlenervepalsieshasbeenattributedtovascularischemiaortraumaticdamage.Femoralandcranialnervesarecommonlyinvolved,andmotorabnormalitiespredominate.48Autonomicneuropathy

thesymptomsincludeanhidrosisofthelowerlimbsorhyperhidrosisoftheupperhalfofthebody,orthostatichypotension,diarrhoea,constipation,urinaryretentionandsexualdysfunction49B.Acutecomplication

Diabeticketoacidosis

Hyperglycemichyperosmolarstatus

50(2)Infection:thisiscommonindiabetespatients,particularlyoftheurinarytractandskin.Tuberculosisandmoniliasisaremorecommonindiabetes.

5152C.Diabeticfoot

Diabeticfootissyndromewhichincludesischemia,peripheralneuropathy,andsecondaryinfection.Occlusivevasculardiseaseinvolvesbothmicroangiopathyandatherosclerosisoflargeandmedium-sizedarteries.

535455HyperglycemiaCanCauseSeriousLong-TermProblems56LaboratoryFindings571.Glucosuria

2.Plasmaglucose

theplasmaglucoselevelafteranovernightfast,normalrangeis3.9-6.0mmol/Lpostprandialplasmaglucoseislessthan7.8mmol/L583.Oralglucosetolerancetest(OGTT)

Ifplasmaglucoseislessthandiagnosticvalueinsuspectedcases,astandardizedOGTTmaybedone.

59

75goralglucoseputinto250-300mlwater,drinkitoverin5minutesandmeasuretheplsamaglucoselevelafter2hours.normalrangeis5.6-7.7mmol/L60615.Glycosylatedhemoglobin(HbA1C)

Sinceglycohemoglobinscirculatewithinredbloodcellswhoselifespanlastsupto120days,theygenerallyreflectthestateofglycemiaoverthepreceding8-12weeks,andprovideanimprovedmethodofassessingdiabeticcontrol.Normalrangeis3-6%.6263GoodNewsforType1Diabetes64GoodNewsforType2Diabetes65DCCTResearchGroup.NEnglJMed.1993;329:977-986.OhkuboY,etal.DiabetesResClinPract.1995;28:103-117.UKPDS33:Lancet1998;352,837-853.StrattonIMetal.BMJ.2000;321:405-412.臨床研究：嚴(yán)格血糖控制

降低糖尿病并發(fā)癥的風(fēng)險(xiǎn)A1cRetinopathyNephropathyNeuropathyCVdiseaseType1DCCT197%63%54%60%41%*

Type2Kumamoto297%69%70%-52%*Type2UKPDS3387%17-21%24-33%-16%**Notstatisticallysignificantduetosmallnumberofevents.

Showedstatisticalsignificanceinsubsequentepidemiologicanalysis466Diagnosis67Recommendationsforthediagnosisofdisordersofglucosemetabolism-----------------------------------------------------------------------------SubjectFPGPPG

---------------------------------------------------------------------------Normal<6.1mmol/L<7.8mmol/LIFG6.1~6.9mmol/L<7.8mmol/LIGT<7.0mmol/L7.8~11.0mmol/L

Diabetes

≥7.0mmol/L

≥11.1mmol/L

HBA1C6.5%-----------------------------------------------------------------------------687698HbA1c(%)10OADmonotherapyDietOADcombinationOAD+basalinsulinOADmonotherapy

uptitrationDurationofdiabetesOAD

+multipledaily

insulininjections傳統(tǒng)的保守的漸進(jìn)的治療手段69GoaloftreatmentofdiabetesDiabetesmellitusrequiresongoingmedicalcareaswellaspatientsandfamilyeducationbothtopreventacuteillnessandtoreducetheriskoflong-termcomplications.70

TargetsfordiabetescontrolGoodAcceptablePoorBloodglucose(mmol/l)Fasting4.4~6.1≤7.0>7.0Postprandial4.4~8.0≤10>10HbA1c(%)<6.56.5~7.0>7.0Totalcholesterol(mmol/l)<4.5≥4.5≥6.0HDLcholesterol(mmol/l)>1.11.1~0.9<0.9Fastingtriglycerides(mmol/l)<1.5<2.2>2.2Bloodpressure(mmHg)<130/80<140/90≥140/90711.Diet

normalweightpersonswithdiabetesusuallyrequireabout35kcal/kgbodyweight/dand0.8-1.2gprotein/kgbodyweight/d.Astandardrecommendationisforfattobe30%orlessoftotalcaloriesandforcarbohydratetobeintherangeof50-60%.72DistributionofnutrientCarbohydrate50-60%Fat30%Protein12-15%7374

Manycliniciansprefertodividefoodintakeintothreemealswith20%ofthecaloriesatbreakfast,40%atlunch,and40%atdinnertimeorfourmealswith28%atbreakfast,28%atlunch,28%atdinnertimeand16%atbedtime.752.Exercise

Regularexerciseisofbenefitfortheoverweightandimprovetheinsulinsensitivityintheobesetype2patients.

76Ontheotherhand,exercisemaycausehypoglycemia,speciallyinthetype1patients.Manycliniciansprefertodoexerciseaftermeals.773.Oraldrug

SulfonylureasMeglitinideanalogsBiguanidesThiazolidinedionesAlpha-glucosidaseinhibitors78藥物根據(jù)作用機(jī)制分類及可能的聯(lián)合磺脲格列柰促進(jìn)受損胰腺分泌胰島素延緩胃腸道碳水化合物的吸收改善外周組織的胰島素抵抗阿卡波糖噻唑烷二酮二甲雙胍胰島素注：根據(jù)作用機(jī)制不同，常用的降糖藥分為胰島素、胰島素促泌劑、胰島素增敏劑和糖苷酶抑制劑四大類——Joslin糖尿病學(xué)（14版）補(bǔ)充胰島素79Sulfonylureas80mechanismofaction

Sulfonylureasstimulateinsulinsecretion.TheyspecificallybindtoareceptorthatclosesanATP-sensitivepotassiumchannelofthepancreaticBcell,therebydepolarizingthecellmembrane.81

Thisresultsinaninfluxofextracellularcalciumthroughvoltage-gatedcalciumchannels,whichcausesinsulingranulestomovetowardthecellsurface,facilitatingexocytosis.82indication

Nonobesetype2patientsthatcan’tcontroltheirglucoselevelthroughdiet,exerciseandwithoutacutecomplications.83contraindicationType1DMGestationalDMType2DMwithseverecomplicationDuringthecourseofsurgeryPancreaticexcisionHepaticorrenalimpairment84AdversereactionHypoglycemiaSkinrashesLeukopenia,thrombopeniaNausea,vomiting85ClassicdrugsGlyburideGlipizideGliclazideGliquidoneGlimeperide86

劑量范圍日服藥生物半作用時(shí)間(h)

（mg/d)次數(shù)衰期(h)開始最強(qiáng)持續(xù)Tolbutamide500~30002~34~80.54~66~12Glybride2.5~151~210~160.52~616~24Glipizide5~301~23~611.5~212~24Gliclazide80~2401~212512~24Gliquidone30~1801~210~20Glimeperide1~61910~2087Meglitinideanalogs88Themechanismofactionofrepaglinideissimilartothesulfornylurea.Itisrapidlyabsorbedfromtheintestineandthenundergoescompletemetabolismintheliver,givingitaplasmahalf-lifeoflessthan1hours.89

Thereisatrendtowardlesshypoglycemiacomparedwithsulfonlyureas.90Biguanides

Biguanides91mechanismofaction

TheBiguanideslowersbloodglucosemainlythroughdiminishedhepaticgluconeogenesisandimprovedtheuseofglucoseinperipheraltissues.92indicationobesetype2DMeitheraloneorinconjunctionwithsulfonylureas93contraindicationHepaticorrenalimpairmentPregnancyAcutecomplication94AdversereactionLacticacidosisNausea,vomitingClassicdrugsMetformin95Alpha-glucosidaseinhibitors96mechanismofaction

Thealpha-glucosidaseinhibitorscompetitivelyinhibitsthealpha-glucosidaseenzymesinthegutwhichdigestdietarystarchandsucrose.

97Thisdrugdelaystheabsorptionofcarbohydratetolowerpostprandialhyperglycemia.98Indication

type2DMwithpostprandialhyperglycemiaContraindication

gastrointestinaldiseasepregnancy99Adversereaction

AbdominaldistentionDiarrhoeaClassicdrugs

Acarbose

100Thiazolidinediones

101mechanismofaction

Thedrugssensitizeperipheraltissuestoinsulin.Theybindanuclearreceptorcalledperoxisomeproliferators-activatedreceptorgamma(PPAR-γ)andaffectexpressionofanumberofgenes.Theexactmechanismisnotknown.102Indication

type2DMwithinsulinresistanceAdversereaction

EdemaContraindication

heartfailure

Hepaticorrenalimpairment103ClassicdrugsPioglitazoneRosiglitazone1044.InsulinTherapyIndication(1)type1DM(2)Diabeticketoacidosis,hyperglycemiahyperosmolarstatus,Lacticacidosis(3)Withinfection,severechroniccomplication105(4)traumaorsurgery(5)pregnancy(6)Pancreaticexcision(7)type2diabeticpatientswhosehyperglycemiadoesnotrespondtodiettherapycombinedwithoraldrugs106AdversereactionHypoglycemiaEdemaHypersensitiveresponse

pruritus,skinrashes107Classicdrugs

regularinsulinneutralprotaminehagedornprotaminezincinsulin108Insulinanalogue1.rapid-actinginsulinanalogsinsulinlisproinsulinaspart2.long-actinginsulinanalogsinsulinglargine109

Inalltypesdiabetesmellitus,eitheroraldrugsorinsulintherapyshouldstartfromminimumdosageandslowlyraisethedoseaccordingtothelevelofplasma

glucose.110

Ifinsulinorsulfonylureasinvolvingmeglitinideanalogscombinedwithbiguanides,alpha-glucosidaseinhibitors,orthaizolidinedionescanincreasetotreathyerglycemiaandmightincreasetheriskofhypoglycemia.111

Ifthefastingplasmaglucoseisalwayshigh,followcausesneedtobeconsidered:

(1)theinsulinororaldrugofnightisnotenough

112(2)dawnphenomenon

thebloodglucoseinnightisnormal,buthyperglycemiaappearsindawnbecauseoftheanti-insulinhormoneincreases.

113(3)Somogyiphenomenon

thereishypoglycemiainnight,andsecondaryhyperglycemia.Monitoringthebloodglucosehelptodetectthecauseofmorninghyperglycemia.114Diabeticketoacidosis115GeneralConsiderations1.Theinitialmanifestationoftype1diabetes2.duringthecourseofinfection,trauma,myocardialinfarction,orsurgery,gestation116Clinicalfinding1.Symptomsandsigns

polyuria,polydipsiaassociatedwithmarkedfatigue,nauseavomiting,andfinallymentalstuporthatcanprogresstocoma

117rapiddeepbreathingandafruitybreathodorofacetone

dehydrationandhypotension

118abdominalpainandtendernessmaybepresentintheabsenceofabdominaldisease1192.LaboratoryfindingHyperglycemia>13.9mmol/LAcidosiswithbloodPH<7.35Serumbicarbonate<18mmol/LUrinepositiveforketones120

SerumpotassiumisnormalorhighdespitetotalbodypotassiumdepletionresultingfrompolyuriaorvomitingSerumcreatinineandureanitrogenmaybemildhighLeukocytosismayoccurwithorwithoutassociatedinfection121Treatment1.PreventionEducationofdiabetic

patientstorecognizetheearlysymptoms

andsignsofketoacidosis122

Urineketones

shouldbemeasuredinpatientswithsigns

ofinfectionorbloodglucoseis

unexpectedlyandpersistentlyhigh.Thepatient

shouldbeinstructedtocontactthephysician

ifketonuriapersists1232.EmergencyMeasuresTherapeuticflowsheetInsulinreplacementFluidreplacementelectrolytereplacementTreatmentofcomplication124Therapeuticflowsheet1.vitalsigns2.diagnostic

laboratoryvalues:urineketonesarterialpHplasmaglucosebicarbonateserumureanitrogenelectrolytesandserumosmolality

1253.Anindwellingurinarycatheterandgastricintubationisrequiredinallcomatosepatientsbutshouldbeavoidedincooperativediabeticbecauseoftheriskofintroducingbladderinfection.1264.Fluidintakeandoutputshouldberecorded.5.Thepatientshouldnotreceivesedativesornarcotics.127InsulinreplacementOnlyregularinsulinshouldbeusedinitiallyinallcasesofsevereketoacidosis,anditshouldbegivenimmediatelyafterthediagnosisisestablished.128Continuouslow-doseinsulininfuseby0.1unit/kg/h,Iftheplasmaglucoselevelfailstofallatleast10%inthefirsthour,thisrequiresdoublingtheinsulindose.

129Measureplasmaglucose,acetone,bicarbonate,serumureanitrogen,andelectrolytesper2hour.130Whenbloodglucosefallsto13.9mmol/Lorless,5%glucosesolutionsshouldbeusedwhileinsulintherapyiscontinuedinordertocleartheketonemia.

131Whenurineketones

hasbecleared,regularinsulinshouldbegiveninhypo.132Fluidreplacement

Inmostpatients,thefluiddeficitis4-5L.Initially,0.9%salinesolutionisthesolutionofchoicetohelpreexpandthecontractedvascularvolumeandshouldbestartedintheemergencyroomassoonasthediagnosisisestablished.133

Inthefirsthour,atleast1Lof0.9%salineshouldbeinfused,andfluidshouldbegiventhereafteratarateof300-500ml/hwithcarefulmonitoringofserumpotassium.

134Whenbloodglucosefallsto13.9mmol/Lorless,5%glucosesolutionsshouldbeusedwhileinsulintherapyiscontinuedinordertocleartheketonemia135electrolytereplacement1.Theuseofsodiumbicarbonate

SodiumbicarbonatemaybeusedwhenthebloodPHislessthan7.1orbloodbicarbonateisbelow6.7mmol/L.OncethePHreaches7.1,nofurtherbicarbonateshouldbegiv