Diabetes Mellitus

1. Diabetes Mellitus Endocrinology Department, Renji Hospital 陶 弢

2. 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.

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

4. Epidemiology Global prevalence of diabetes

5. Epidemiology 糖尿病患者前10位的国家 排名 国家 1995(百万) 国家 2025(百万) 57.2 37.6 21.9 14.5 12.4 12.2 11.7 11.6 8.8 8.5 103.6 300.0 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 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 1 2 3 4 5 6 7 8 9 10 Total 19.4 16.0 13.9 8.9 6.3 4.9 4.5 4.3 3.8 3.6 49.7 135.3 King H, et al. Diabetes Care 1998;21:1414–31.

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

7. 一 . Type 1 diabetes (T1DM) βcell destruction, usuallyleading to absoluteinsulin 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. Idiopathicclinical 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

8. 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

9. 二. Type 2 diabetes (T2DM) 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

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

11. Other specific types 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

12. 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

13. 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

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

15. 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

16. Etiology and pathogenesis

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

18. 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 • TNFβand 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

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

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

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

22. 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)

23. Pathophysiology of DM

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

25. Clinical featureof DM

26. Etiological factor type of diabetes clinical stage

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

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

29. 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%

30. Diagnostic criteria (1999, WHO)

31. The diagnostic criteria for diabetes mellitus

32. To differentiate type 1DM and type2DM

33. 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?

34. Chronic complication Macrovascular (CHD, CVD, PVD) -metabolic syndrome-IR Microvascular (kidney, reticular, nerve) -thickening of the capillary basement membrane

35. 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)

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

37. 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 theretinopathy is extensive or is preproliferative or preliferative,the patient should be evaluated for treatment by photocogulation

38. 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

39. Background Diabetic Retinopathy Hard exdates Dothemorrhages

40. Proliferative Diabetic Retinopathy

41. 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

42. 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

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

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

45. Target(2002,Asia-Pacific area) • idealacceptablebad • 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

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

47. 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%

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

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

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