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1、Diabetes MellitusDepartment of PathophysiologyWuhan University School of Medicine1Definition Diabetes mellitus is a heterogeneous primary disorder of carbohydrate metabolism with multiple etiologic factors that generally involve absolute or relative insulin deficiency or both. All causes of diabetes
2、 ultimately lead to hyperglycemia, and it can causes the late complications involving the eyes, kidneys, nerves and blood vessels. 2Environmental-Genetic interactionsAbsolute or relative insulin deficiencyDisorder of carbohydrate, protein and fat metabolismhyperglycemiaComplications involving the ey
3、es,kidneys,nerves and blood vessels病因病因发病机制发病机制病理生理病理生理共同特征共同特征最终结局最终结局3EpidemiologyGlobal prevalence of diabetes 4 1 2 3 4 5 6 7 8 910 Total印度印度中国中国美国美国俄联邦俄联邦日本日本巴西巴西印度尼西亚印度尼西亚巴基斯坦巴基斯坦墨西哥墨西哥Ukraine所有其他国家所有其他国家 19.4 16.0 13.9 8.9 6.3 4.9 4.5 4.3 3.8 3.6 49.7135.3印度印度中国中国美国美国巴基斯坦巴基斯坦印度尼西亚印度尼西亚俄联邦俄联邦墨
4、西哥墨西哥巴西巴西埃及埃及日本日本所有其他国家所有其他国家 57.2 37.6 21.9 14.5 12.4 12.2 11.7 11.6 8.8 8.5103.6300.0糖尿病患者前糖尿病患者前糖尿病患者前糖尿病患者前1010位的国家位的国家位的国家位的国家排名排名国家国家国家国家1995(百万百万)2025(百万百万)King H, et al. Diabetes Care 1998;21:141431.Epidemiology5ClassificationEtiologic classification of diabetes mellitus(1997 ADA 1999 WHO)Ty
5、pe 1 diabetes (T1DM)Other specific typesType 2 diabetes(T2DM)Gestation diabetes mellitus(GDM)6cell destruction, usually leading to absolute insulin deficiency A. Immune mediated 1) being rapid, mainly in infants and children 2) being slow, mainly in adults-latent autoimmune diabetes in adults, LADA
6、B. Idiopathic clinical feature obviously family history , early onset, at the beginning having ketosis, need a small quantity insulin therapy; cell destruction slowly progressing , after onset several months or years not need insulin therapy一一 . Type 1 diabetes (T1DM)7LADA Clinical feature1.Called t
7、ype 1.5 DM or slowly progressing insulin-dependent diabetes2.T cell mediated autoimmune disease3.Adult age at diagnosis (range 30-70year)4.Lean or non-obesity5.The presence of diabetes-associated autoantibodies(IA2, ICA, GAD )6.Delay (at least half year )from diagnosis in the need for insulin therap
8、y to manage hyperglycemia 7.Having type 1 DMs predisposing genes( such as HLA-DR3,HLA-DR4,BW54, DQ-131-57-NON-ASP etal)8.Often accompany thyroid and gastric parietal cells organ specific antibody8 may range from predominantly insulin resistance with relative insulin deficiency to a predominantly sec
9、retory defect with insulin resistanceThe risk of developing this form of diabetes increases with age, obesity and lack of physical activityIt is often associated with a strong genetic predisposition, more than is the type 1 diabetes higher prevalence二二. Type 2 diabetes (T2DM)9三三. Other specific type
10、s Divided into 8 subgroups according to the etiology and pathogenesis, including all the secondary diabetes and specific etiologic diabetes10Genetic defects of B cell functionMaturity-onset diabetes of the young (MODY) 1). Chromosome 20,HNF-4a (MODY1) 2). Chromosome 7p,glucokinase (MODY2) 3). Chromo
11、some 12,HNF-1a (MODY3) 4). Insulin promoter factor 1,IPF-1(MODY4) 5). Chromosome 17 cen-q , HNF-1 (MODY5) 6). Chromosome 2q,NEUROD4 (MODY6) 7). Mitochondrial DNAOther specific types11MODY Clinical featureEarly onset, at least one patient develops Diabetes before the age of 25 Autosomal Dominant Inhe
12、ritance , disease deliver fit Mendelian inheritance ; having three generation or above family constellation heredity historyDiabetes may be treated by diet or tablets and does not always need insulin treatment 12Mitochondrial maternal inheritance diabetes clinical featureMaternal inheritance; means
13、children of female patient possible with disease, children of male patient not with diseaseEarly onset, Lean or non-obesityDiabetes may be treated by diet or tablets and does not always need insulin treatment at initial stage, no prone to ketosis; but in the long run, need for insulin therapy to man
14、age hyperglycemia Often accompany dysaudia in prediabetes or afterdiabetes Minority having manifestation damaged by (nerve, muscle, retina hematopoietic system, et al) or serum lactic acid raising up13Other specific typesGenetic defects of insulin actionType A insulin resistance( ovarian hyperandrog
15、en insulin resistant acanthosis nigrican HAIR-AN )Rabson-Mendenhall syndrome LeprechaunismLipoatrophic diabetes Disease of exocrine pancreas Endocrinopathies Drug or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes14四四.
16、 Gestation diabetes mellitus(GDM)Diabetes and IGR(糖调节受损) be diagnosed during the gestationScreening the GDM during gestation 2428 weeks through OGTT 50g glucose test -screen test 100g glucose test -diagnostic test High-risk group, age25y or age25y but obesity, direct relative of DM6 weeks after part
17、urition, OGTT be given again 15Etiology and pathogenesis16Type 1 DMProne to ketoacidosisAbsolute insulin deficiency(ID)(Low C-peptide level)-cell destructionidiopathyGenetic susceptibilityEnviromental factors initiateGADA,IAA,ICAIA2 and IA-2HLA-DR/DQautoimmune (Virus infection, chemical, diet)17HLA
18、and autoantibodiesHLA (histocompatibility locus antigen)-major effective geneHLA DR3,-DR4-background conditionHLA DQ-B57-Asp- resistance geneHLA DQ-B57-Val/Ala/Ser;DQ-A52-Arg-predisposing genesTNF and hsp70(heat shock protein 70) gene polymorphismAutoantibody :GADA (antibody to glutamic acid decarbo
19、xylase)- -cell destruction early markerICA (islet cell autoantibody)specificity lowIAA (autoantibody to insulin) specificity lowIA-2 ( autoantibody to tyrosine phosphatases IA-2 andIA-2)-specificity high18Type 2 DMGenetic susceptibility Enviromental factors( obese, rich diet ,oldLess physical activi
20、ty )Insulin deficiency(ID)Insulin resistance(IR)IGR(糖调节受损) (IGT(糖耐量受损糖耐量受损 ), IFG(空腹血糖受损空腹血糖受损 )T2DMLow born weight19Insulin resistance : definitionInsulin sensitivity The ability of insulin to degrade dissociation glucose concentration stimulate to utilize glucose: muscle and fat inhibit to generat
21、e glucose: liverInsulin resistance Lossing insulin sensitivity lead to hyperinsulinemia 20insulin resistance endodermis functional disturbanceAccelerate to generate atherosclerosiscardiovascular diseaseType 2 DMIGTIGTHyperinsulinemiab b b b-cell -cell decompensationdecompensationMicrovascularcomplic
22、ationCentral obesityhypertension hypertriglyceridemia HDL cholesterol plasminogen System dysfunctionpolycystic ovarian syndromeCusi K, Cusi K, Diabetes Care, 2000Diabetes Care, 2000mechanism of action21Relative gene Insulin resistance insulin receptor substance 1 and 2 di-allelic mutation glucose tr
23、ansporter -4(GLUT-4) genetic mutation insulin receptor already detected fifty mutable site uncoupling protein (UCP) genetic mutationInsulin deficiency glucokinase (GCK) glucose transporter -2(GLUT-2) mitochondria defect proinsulin processing disorder insulin structural abnomalities islet amyloid pol
24、ypeptide( IAPP) 22Pathophysiology of DM23Insulin deficiencyIRCharacterized by hyperglycemiaAccompanied by disruption of protein , lipid , water and electrocytes metabolismGlucogen synthesis Glucose oxidation Glucogen catabolism Hepatic glucose production Adipocytes uptake TG Lipid synthesis (lipopro
25、teinesterase activity )Lipid mobilization (Hormone sensitive lipase )ketone (acetone, acetoacetic acid,beta-hydroxybutyric acid)24Clinical feature of DM25 Stage TypeEugly-caemia HyperglycemianormalregulationIGT IFG Diabetes mellitusdont need need insulin insulin insulin sustained Type 1 Type 2 Speci
26、fic GDMEtiological factor type of diabetes clinical stage26Insulin deficiency Insulin resistancehyperglycemiadisruption of protein , lipid , water and electrocytes metabolism Chronic impairment : Macrovascular (CHD, CVD, PVD)Microvascular (kidney, reticular, nerve)osmotic diuresispolyuria(多尿多尿), Thi
27、rst(口渴口渴),Polydipsia(多饮多饮)Polyphagia(多食多食)Weight loss(消瘦消瘦)Visiual blurringVulvovagitis and pruritus(瘙痒瘙痒)27Insulin deficiency Insulin resistancehyperglycemiaOGTT+C-peptide/insulinUrine glucose ( for monitoring)blood glucose ( for diagnosis and monitoring)HbA1c ( for monitoring)Urine/blood ketoneLab
28、 testhypoinsulinemiahyperinsulinemia28HbA1c Glucose sticks to the haemoglobin to make aglycosylated haemoglobin molecule, called haemoglobin A1C or HbA1C. By measuring the HbA1C it can tell you how high your blood glucose has been on average over the last 8-12 weeks. Measuring the HbA1C by affinity
29、chromatography and high efficiency liquid chromatography Normal range :4%-6%29Diagnostic criteria (1999, WHO) Plasma glucose (mmol/L) FPG(空腹血糖 ) PPG(餐后血糖 ) OGTT 2hNormal range 6.1 and 7.8Diabetes mellitus 7.0 or 11.1 or 11.1 IGR IFG 6.1 - 7.0 7.8 IGT 7.0 7.8 - 11.130 1. Classic symptom plus casual p
30、lasma glucose 11.1mmol/L, casual is defined as any time of day without regard to time since last meal or2. An overnight fasting glucose (FPG) 7.0 mmol/L, Fasting is defined as no caloric intake for at least 8 hours or 3. 2 h PG 11.1mmol/L during an OGTT. If without classic symptom,each must be confi
31、rmed,on a subsequent day, by any one of the three methods given as aboveThe diagnostic criteria for diabetes mellitus31To differentiate type 1 DM and type 2 DMType 1 DMTpye 2 DMOnset modeacuteChronic and delitescenceOnset ageYoung(40 years old(60-65y)Clinical featuretypical and severityLight or asym
32、ptomsketoacidosisspontaneouslyUsually having remote cause(infection etal)Insulin or C-peptide release testLow or Deficiency peak value delay or absenceOnset body weight Normal or tabificationOverweight or obesity Chronic impairmentNephropathy(35%-40%-mainly death cause)Cardiovascular Disease(70%- ma
33、inly death cause)TreamentinsulinOral hypoglycemia agents/insulin32 LADA diagnose keypoint1.Onset after 20y, clinical symptom (polyurine, polydipsia, polyphagia, weight loss) obviously, BMI16.5mmol/l2.Fasting Cpeptid0.4nmol/l ,OGTT1h and/or 2h Cpeptid0.8nmol/l ,curve low and equal3.GADA()4.HLA-DQ B57
34、 non-Asp homozygote5. 1 add 2/3/4-LADA?33 Chronic complication Macrovascular (CHD, CVD, PVD) -metabolic syndrome-IRMicrovascular (kidney, reticular, nerve) -thickening of the capillary basement membrane34 Macrovascular morbidity rate high young age of onsetpathogenetic condition progress quicklyMult
35、iorgan to be involved inmainly death cause in type 2 DMintermittent lameness (间歇性跛行)35 MicrovascularMarkable change: microcirculation disturbance micro-angioma to shape microangium basal membrane thickeningCentre component element: HyperglycemiaPathogenesis 36 Diabetic retinopathyNon-proliferation I
36、f evidence of mild nonproliferation retinopathy is present, the current recommended approach is frequent evaluation through repeated ophthalmic examinations Proliferation If the retinopathy is extensive or is pre-proliferative or preliferative, the patient should be evaluated for treatment by photoc
37、ogulation37Diabetic Retinopathy（China：1984）backgroundbackgroundI microaneurysms and/ or dot hemorrhagesII hard exudates and/ or dot hemorrhagesIII soft exudates and/ or dot hemorrhagesproliferationproliferationI growth of abnormal blood vessels and/ or vitreous hemorrhages II growth of abnormal bloo
38、d vessels and fibrous tissue III growth of abnormal blood vessels and fibrous tissue, detachment of the retina38Background Diabetic RetinopathyHard exudates(硬性渗出 )Dot hemorrhages 39Proliferative Diabetic Retinopathy 40 Diabetic nephropathyI: hypertrophy, hyperfiltrationII: micro-albuminura after exe
39、rcise (UAER: 20- 200ug/min or UA 30-300 mg/24h)III: continuity microalbuminura IV: macroalbuminura (UAER200ug/min or UA 300 mg/24h) edema and hypertensionV: ESRD (终末期肾病 )UAER: 尿蛋白质排泄率 41 Diabetic neuropathyPeripheral poly-neuropathy (symmetry /multiple/slowly progressing/lower limb severity)Mono-neu
40、ropathy (oculomotor nerve/ abducent nerve)Autonomic neuropathy (stomach intestine/ urinary system/ sexual organ/ cardiovascular system)Skininfection42 Acute complicationDiabetic Ketone acidosis (DKA)Non-ketone diabetic-hyperosmal coma ( NKDC)Lactate acidosisHypoglycemic coma43TreatmentEarly, long te
41、rm, integrated, individualizedDiet controlPhysical activityDrug therapyEducationSelf-monitoring44 Target(2002, Asia-Pacific area)45DietTotal calorie control (ideal bodyweight)Carbohydrate (50-60%) Protein(15-20%) Lipid(20-25%)Distribution ( eg. 1/5, 2/5,2/5)46Lifestyle modification生活方式干预生活方式干预生活方式干预
42、生活方式干预- eat less, walk more- eat less, walk more1. 1.30 minutes, moderate exercise, 5/7days30 minutes, moderate exercise, 5/7days2. 2.Health dietHealth diet3. 3.Weight lossWeight loss4. 4.Lifestyle modification (Finland)Lifestyle modification (Finland)5. 5.Weight loss 2.4kg in 5 years, T2DM decrease
43、d 58%Weight loss 2.4kg in 5 years, T2DM decreased 58%6. 6.DPPDPP7. 7.Weight loss 4.3kg in 3 years, T2DM decreased 58%Weight loss 4.3kg in 3 years, T2DM decreased 58%47Oral hypoglycemic agentsSulfonylureas glyburide, glipizide, glimeperide Glinides retaglinide，nateglinid Biguanides metformin glucosid
44、ase inhibitor acarbose, miglitol ,voglibose Thiazolidiones rosiglitazone, pioglitazone 48Mechanism of action-MFInsulin secretion burdenInsulin secretion burdenHepatic outputHepatic output控制血糖控制血糖Glucose uptakeGlucose uptakemusclemusclepancreaspancreasliverliverAmerican Diabetes Association.Medical M
45、anagement of Non-Insulin-Dependent(Type2) Diabetes.3rd et.Alexandria,VA: American Diabetes Association:199449Mechanism of action-TZDAgonists of Agonists of PPARPPAR(peroxisome proliferator activated receptor)(peroxisome proliferator activated receptor)50Indication of insulin therapy1.T1DM2.T2DM: Acu
46、te complication: NHDC, DKA, LA End stage of chronic complication Stress Pregnancy SU Failure Severe weight loss Cortisol therapy51Insulin therapyFasting hyperglycemiainsulin deficiency (waning of circulating insulin levels)Somogyi phenomenaDawn phenomena52HyperglycemiaInsulin levelInsulin sensitivit
47、y-cellSU(AC 30)Benzoic acid derivatives(AC 0-5)insulinBiguanidesThiazolidinedioneshepaticMuscle,adipocyte -glucosidase inhibitor53STEP-WISE STRATIGE Matthaei S, et al. Endocr Rev 21:585,2000EDUCATIONDIETEXERCISEMFTZDSUinsulin80 120 160 200FPG (mg/dl)100806040200mean insulin during OGTT (mU/l)54Pregn
48、ancyDietExerciseInsulin therapy55DKA (酮症酸中毒 )56Precipitating factorsMost common: infectionCerebrovascular accidentAlcohol abusePancreatitisMyocardial infarctionTraumaDrugs (corticosteroids, thiazides,sympathomimetic agents) 57Lab Test58Treatment59Insulin therapy-Exclude hypokalemia (K3.3 mEq/l)Intra
49、venous bolus of RI at 0.15 units/kgFollowed by continuous infusion 0.1U/kg/hTarget: 1st h BG2.8-4.2mmol/lor check hydration, if acceptableDoubled insulin fusion BG14mmol/l, insulin 0.05-0.1U/kg/h+5-10%GSKeep BG-14mmo/l,until acidosis in DKA or mental obtundation and hyperosmolarity in HHS are resolv
50、ed.When pt can eat,0.5-1.0U/kg/d H(2/3 in AM, 1/3 in PM)60Fluid therapy -Adult patientsAim: expansion of the intravascular and extravascular volume and restoration of renal perfusion.1st h: 0.9% NS 15-20ml/kg/h1-1.5lThen 4-14 ml/kg/h 200-700ml0.9%NSserum Na low0.45%NS serum Na high/normalJudged by h
51、emodynamic monitoring(Bp), measurement of fluid output and input, and clinical examination.Avoid iatrogenic fluid overload50ml/kg over first 4hReplace fluid deficit evenly over 48hOsmolality decreased less than 3mOsm/kg.H2O.h61POTASSIUM3.3mM, avoid insulin therapy5.5mM, start Ka supplement20-30mEq/l10% KCl 20ml/lAim 4-5mEq/l62NHDC (非酮症性高渗性糖尿病昏迷非酮症性高渗性糖尿病昏迷 )63思 考 题 简述如何诊断和治疗糖尿病。简述1性糖尿病和2性糖尿病的主要区别。64个人观点供参考，欢迎讨论
