Diabetes mellitus PowerPoint Presentation

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Diabetes Mellitus Endocrinology Department, Renji Hospital 陶 弢

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Definition 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 ultimately lead to hyperglycemia, and it can causes the late complications involving the eyes, kidneys, nerves and blood vessels.

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Environmental-Genetic interactions Absolute or relative insulin deficiency Disorder of carbohydrate, protein and fat metabolism hyperglycemia Complications involving the eyes,kidneys,nerves and blood vessels 病因 发病机制 病理生理 共同特征 最终结局

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Epidemiology Global prevalence of diabetes

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1 2 3 4 5 6 7 8 9 10 Total 印度 中国 美国 俄联邦 日本 巴西 印度尼西亚 巴基斯坦 墨西哥 Ukraine 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 49.7 135.3 印度 中国 美国 巴基斯坦 印度尼西亚 俄联邦 墨西哥 巴西 埃及 日本 所有其他国家 57.2 37.6 21.9 14.5 12.4 12.2 11.7 11.6 8.8 8.5 103.6 300.0 糖尿病患者前10位的国家 排名 国家 国家 1995 (百万) 2025 (百万) King H, et al. Diabetes Care 1998;21:1414–31. Epidemiology

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Classification Etiologic classification of diabetes mellitus (1997 ADA 1999 WHO) Type 1 diabetes (T1DM) Other specific types Type 2 diabetes(T2DM) Gestation diabetes mellitus(GDM)

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βcell 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 B. Idiopathic clinical feature obviously family history , early onset, at the beginning having ketosis, need a small quantity insulin therapy; βcell destruction slowly progressing , after onset several months or years not need insulin therapy 一 . Type 1 diabetes (T1DM)

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LADA– Clinical feature Called type 1.5 DM or slowly progressing insulin-dependent diabetes T cell mediated autoimmune disease Adult age at diagnosis (range 30-70year) Lean or non-obesity The presence of diabetes-associated autoantibodies(IA2, ICA, GAD ) Delay (at least half year )from diagnosis in the need for insulin therapy to manage hyperglycemia Having type 1 DM’s predisposing genes( such as HLA-DR3,HLA-DR4,BW54, DQ-131-57-NON-ASP etal) Often accompany thyroid and gastric parietal cells organ specific antibody

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may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance The risk of developing this form of diabetes increases with age, obesity and lack of physical activity It is often associated with a strong genetic predisposition, more than is the type 1 diabetes higher prevalence 二. Type 2 diabetes (T2DM)

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三. Other specific types Divided into 8 subgroups according to the etiology and pathogenesis, including all the secondary diabetes and specific etiologic diabetes

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Genetic defects of B cell function Maturity-onset diabetes of the young (MODY) 1). Chromosome 20,HNF-4a (MODY1) 2). Chromosome 7p,glucokinase (MODY2) 3). Chromosome 12,HNF-1a (MODY3) 4). Insulin promoter factor 1,IPF-1((MODY4) 5). Chromosome 17 cen-q , HNF-1ß (MODY5) 6 ). Chromosome 2q,NEUROD4 (MODY6) 7). Mitochondrial DNA Other specific types

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MODY Clinical feature Early onset, at least one patient develops Diabetes before the age of 25 Autosomal Dominant Inheritance , disease deliver fit Mendelian inheritance ; having three generation or above family constellation heredity history Diabetes may be treated by diet or tablets and does not always need insulin treatment

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Mitochondrial maternal inheritance diabetes clinical feature Maternal inheritance; means children of female patient possible with disease, children of male patient not with disease Early onset, Lean or non-obesity Diabetes 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 manage 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 up

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Other specific types Genetic defects of insulin action Type A insulin resistance( ovarian hyperandrogen insulin resistant acanthosis nigrican HAIR-AN ) Rabson-Mendenhall syndrome Leprechaunism Lipoatrophic diabetes Disease of exocrine pancreas Endocrinopathies Drug or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes

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四. Gestation diabetes mellitus(GDM) Diabetes and IGR be diagnosed during the gestation Screening the GDM during gestation 24—28 weeks through OGTT 50g glucose test -----screen test 100g glucose test -----diagnostic test High-risk group, age>25y or age<25y but obesity, direct relative of DM 6 weeks after parturition, OGTT be given again

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Etiology and pathogenesis

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Type 1 DM Prone to ketoacidosis Absolute insulin deficiency(ID) (Low C-peptide level) β-cell destruction idiopathy Genetic susceptibility Enviromental factors initiate GADA, IAA, ICA IA2 and IA-2β HLA-DR/DQ autoimmune (Virus infection, chemical, diet)

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HLA and autoantibodies HLA (histocompatibility locus antigen)---major effective gene HLA –DR3,-DR4-----background condition HLA –DQ-B57-Asp---- resistance gene HLA –DQ-B57-Val/Ala/Ser;DQ-A52-Arg---predisposing genes TNFβ and hsp70(heat shock protein 70) gene polymorphism Autoantibody : GADA (antibody to glutamic acid decarboxylase)--- β-cell destruction early marker ICA (islet cell autoantibody)—specificity low IAA (autoantibody to insulin) —specificity low IA-2 ( autoantibody to tyrosine phosphatases IA-2 andIA-2β)---specificity high

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Type 2 DM Genetic susceptibility Enviromental factors ( obese, rich diet ,old Less physical activity ) Insulin deficiency(ID) Insulin resistance(IR) IGR (IGT, IFG) T2DM Low born weight

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Insulin resistance : definition Insulin sensitivity The ability of insulin to degrade dissociation glucose concentration stimulate to utilize glucose: muscle and fat inhibit to generate glucose: liver Insulin resistance Lossing insulin sensitivity lead to hyperinsulinemia

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insulin resistance endodermis functional disturbance Accelerate to generate atherosclerosis cardiovascular disease Type 2 DM IGT Hyperinsulinemia b-cell decompensation Microvascular complication Central obesity hypertension hypertriglyceridemia HDL cholesterol plasminogen System dysfunction polycystic ovarian syndrome Cusi K, Diabetes Care, 2000 mechanism of action

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Relation gene Insulin resistance insulin receptor substance 1 and 2 di-allelic mutation glucose transporter -4(GLUT-4) genetic mutation insulin receptor already detected fifty mutable site uncoupling protein (UCP) genetic mutation Insulin deficiency glucokinase (GCK) glucose transporter -2(GLUT-2) mitochondria defect proinsulin processing disorder insulin structural abnomalities islet amyloid polypeptide( IAPP)

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Pathophysiology of DM

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Insulin deficiency IR Characterized by hyperglycemia Accompanied by disruption of protein , lipid , water and electrocytes metabolism Glucogen synthesis  Glucose oxidation  Glucogen catabolism  Hepatic glucose production Adipocytes uptake TG  Lipid synthesis  (lipoproteinesterase activity ) Lipid mobilization (Hormone sensitive lipase ) ketone (acetone, acetoacetic acid, beta-hydroxybutyric acid)

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Clinical feature of DM

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Etiological factor type of diabetes clinical stage

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Insulin deficiency Insulin resistance hyperglycemia disruption of protein , lipid , water and electrocytes metabolism Chronic impairment : Macrovascular (CHD, CVD, PVD) Microvascular (kidney, reticular, nerve) osmotic diuresis polyuria(多尿), Thirst(口渴), Polydipsia(多饮) Polyphagia(多食) Weight loss(消瘦) Visiual blurring Vulvovagitis and pruritus(瘙痒)

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Insulin deficiency Insulin resistance hyperglycemia OGTT + C-peptide/insulin Urine glucose ( for monitoring) blood glucose ( for diagnosis and monitoring) HbA1c ( for monitoring) Urine/blood ketone Lab test hypoinsulinemia hyperinsulinemia

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HbA1c Glucose sticks to the haemoglobin to make a'glycosylated 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 chromatography and high efficiency liquid chromatography Normal range :4%--6%

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Diagnostic criteria (1999, WHO)

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The diagnostic criteria for diabetes mellitus

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To differentiate type 1DM and type2DM

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LADA diagnose keypoint Onset after 20y,clinical symptom(polyurine, polydipsia, polyphagia, weight loss) obviously,BMI<25kg/m2, FBG>16.5mmol/l Fasting Cpeptid≤0.4nmol/l ,OGTT1h and/or 2h Cpeptid≤0.8nmol/l ,curve low and equal GADA(＋) HLA-DQ B57 non-Asp homozygote 1 add 2/3/4------LADA?

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Chronic complication Macrovascular (CHD, CVD, PVD) -metabolic syndrome-IR Microvascul -thickening of the capillary basement membrane

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Macrovascular morbidity rate high young age of onset pathogenetic condition progress quickly Multiorgan to be involved in mainly death cause in type2 DM intermittent lameness (间歇性跛行)

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Microvascular Markable change: microcirculation disturbance microangioma to shape micrangium basal membrane thickening Centre component element: Hyperglycemia Pathogenesis

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Diabetic retinopathy Non-proliferation If 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 preproliferative or preliferative,the patient should be evaluated for treatment by photocogulation

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Diabetic Retinopathy （China：1984） background I microaneurysms and/ or dot hemorrhages II hard exudates and/ or dot hemorrhages III soft exudates and/ or dot hemorrhages proliferative I growth of abnormal blood vessels and/ or vitreous hemorrhages II growth of abnormal blood vessels and fibrous tissue III growth of abnormal blood vessels and fibrous tissue, detaqchment of the retina

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Background Diabetic Retinopathy Hard exdates Dot hemorrhages

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Proliferative Diabetic Retinopathy

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Diabetic nephropathy I: hypertrophy, hyperfiltration II: microalbuminura after exercise(UAER: 20-200ug/min or UA 30-300 mg/24h) III: continuity microalbuminura IV: macroalbuminura (UAER>200ug/min or UA> 300 mg/24h) edema and hypertension V: ESRD

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Diabetic neuropathy Peripheral polyneuropathy (symmetry /multiple/slowly progressing/lower limb severity) Mononeuropathy (oculomotor nerve/ abducent nerve) Autonomic neuropathy (stomach intestine/ urinary system/ sexual organ/ cardiovascular system) Skin infection

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Acute complication Diabetic Ketone acidosis (DKA) Non-ketone diabetic-hyperosmal coma ( NKDC) Lactate acidosis Hypoglycemic coma

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treatment Early, long term, integrated, individualized Diet control Physical activity Drug therapy education Self-monitoring

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Target(2002, Asia-Pacific area) ideal acceptable bad FVPG < 6.1mmol/L ≤7.0mmol/L >7 mmol/L 2hVPG < 8.0mmol/L ≤10mmol/L >10mmol/L HbA1c < 6.5% 6.5-7.5% >7.5% TG <1.5 mmol/L <2.2mmol/L > 2.2 mmol/L TC < 4.5mmol/L >4.5 mmol/L > 6.0 mmol/L LDL-C < 2.5 mmol/L < 4.4mmol/L > 4.4 mmol/L HDL-C > 1.1 mmol/L 0.9-1.1mmol/L < 0.9 mmol/L BP < 130/80mmHg >130/80-<140/90 > 140/90 BMI M < 25 <27 ≥ 27 F < 24 <26 ≥26

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Diet Total calorie control (ideal bodyweight) Carbohydrate (50-60%) Protein(15-20%) Lipid(20-25%) Distribution ( eg. 1/5, 2/5,2/5)

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Lifestyle modification 生活方式干预---- eat less, walk more 30 minutes, moderate exercise, 5/7days Health diet Weight loss Lifestyle modification (Finland) Weight loss 2.4kg in 5 years, T2DM decreased 58% DPP Weight loss 4.3kg in 3 years, T2DM decreased 58%

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Oral hypoglycemic agents Sulfonylureas —— glyburide, glipizide, glimeperide Glinides —— retaglinide，nateglinid Biguanides —— metformin  glucosidase inhibitor —— acarbose, miglitol ,voglibose Thiazolidiones —— rosiglitazone, pioglitazone

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Mechanism of action-SU nateglinide repaglinide (36 kD) SUR depolarization ATP glimipiride（65 kD） glyburide（140 kD） Kir 6.2 SUR

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Mechanism of action-MF ↓Insulin secretion burden ↓Hepatic output 控制血糖 ↑Glucose uptake muscle pancrease liver American Diabetes Association.Medical Management of Non-Insulin-Dependent(Type2) Diabetes.3rd et.Alexandria,VA: American Diabetes Association:1994

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Mechanism of action- acarbose Acarbose Oligosaccharide Acarbose Small intestine mucosa Reversible inhibition of oligosaccharide breakdown by -glucosidases

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Mechanism of action-TZD Agonists of PPARγ (peroxisome proliferator activated receptorγ,)

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Indication of insulin therapy T1DM T2DM: Acute complication: NHDC, DKA, LA End stage of chronic complication Stress Pregnancy SU Failure Severe weight loss Cortisol therapy

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Insulin therapy Fasting hyperglycemia insulin deficiency (waning of circulating insulin levels) Somogyi phenomena Dawn phenomena

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hyperglycemia Insulin level Insulin sensitivity β-cell SU(AC 30’) Benzoic acid derivatives(AC 0-5’) insulin Biguanides Thiazolidinediones hepatic Muscle,adipocyte -glucosidase inhibitor

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STEP-WISE STRATIGE Matthaei S, et al. Endocr Rev 21:585,2000 EDUCATION DIET EXERCISE MF TZD SU insulin mean insulin during OGTT (mU/l)

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pregnancy Diet Exercise Insulin therapy

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Insulin deficiency Rapid mobilization of energy from stores in muscle and fat depots. Ketone production  Insulin-antagonistic hormone Utilization is reduced Ketone is accumulated acidosis Disturbance of electrocyte Nausea vomiting Rapid and deep respiration osmotic diuresis Hyperglycemia polyuria DKA depletion of intravascular volume Precipitating factors: infection , diet, surgery, trauma, pregnancy

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Precipitating factors Most common: infection Cerebrovascular accident Alcohol abuse Pancreatitis Myocardial infarction Trauma Drugs (corticosteroids, thiazides,sympathomimetic agents)

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Insulin deficiency Rapid mobilization of energy from stores in muscle and fat depots Ketone is accumulated Insulin-antagonistic hormone acidosis Disturbance of electrocytes Hyperglycemia Lab test depletion of intravascular volume acetoacetate, B-hydroxybutyrate, acetone HCO3 - , PH  K, Na, Cl Bun  Cr  Precipitating factors:blood count,X-ray,ECG

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Insulin deficiency Insulin-antagonistic hormone Ketone is accumulated acidosis Disturbance of electrocyte Hyperglycemia treatment depletion of intravascular volume Insulin supplement (0.1U/kg/h) Liquid supplement

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Insulin therapy-Exclude hypokalemia(K<3.3 mEq/l) Intravenous bolus of RI at 0.15 units/kg Followed by continuous infusion 0.1U/kg/h Target: 1st h BG2.8-4.2mmol/l or check hydration, if acceptable Doubled insulin fusion BG<14mmol/l, insulin 0.05-0.1U/kg/h+5-10%GS Keep BG-14mmo/l,until acidosis in DKA or mental obtundation and hyperosmolarity in HHS are resolved. When pt can eat,0.5-1.0U/kg/d H(2/3 in AM, 1/3 in PM)

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Fluid therapy -Adult patients Aim: expansion of the intravascular and extravascular volume and restoration of renal perfusion. 1st h: 0.9% NS 15-20ml/kg/h—1-1.5l Then 4-14 ml/kg/h — 200-700ml 0.9%NS—serum Na low 0.45%NS —serum Na high/normal Judged by hemodynamic monitoring(Bp), measurement of fluid output and input, and clinical examination. Avoid iatrogenic fluid overload <50ml/kg over first 4h Replace fluid deficit evenly over 48h Osmolality decreased less than 3mOsm/kg.H2O.h

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POTASSIUM <3.3mM,avoid insulin therapy <5.5mM, start Ka supplement20-30mEq/l 10% KCl 20ml/l Aim 4-5mEq/l

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Partial Insulin deficiency Insulin-antagonistic hormone Serum sodium  osmotic diuresis Hyperglycemia polyuria NHDC dehydration Precipitating factors: infection , diet, cerebrovascular accident, MI Lethargy,confusion hyperosmotality Absence of significant ketosis Coma

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Consideration question How to diagnose and treat Diabetes mellitus ？ How to differentiate type 1DM and type2DM ?

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谢谢！