1. Diabetes Mellitus Zhao XiaoJuan Department of Endocrinology The First Hospital of China Medical University 2007.10.23

2. Adapted from Zimmet P et al. Diabet Med. 2003;20:693-702. 25.0 39.7 59% 25.0 39.7 59% 10.4 19.7 88% 10.4 19.7 88% 38.2 44.2 16% 38.2 44.2 16% 1.1 1.7 59% 1.1 1.7 59% 13.6 26.9 98% 13.6 26.9 98% 81.8 156.1 91% 81.8 156.1 91% 18.2 35.9 97% 18.2 35.9 97% Prevalence of Diabetes Mellitus million 2007 ： 246 000 000 2025 ： 380 000 000 2003 ： 189 000 000 2025 ： 324 000 000 72% 

3. Outline 1. Definition 2. Diagnosis 3. Classification 4. Complications 5. Management

4. 1.Definition  Diabetes mellitus is characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both.

5. 1.Definition  The chronic hyperglycemia of diabetes is associated with long- term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. American Diabetes Association, 2003

6. Outline 1. Definition 2. Diagnosis 3. Classification 4. Complications 5. Management

7. 2. Diagnosis Diagnostic Criteria (WHO 1999)  Symptoms of diabetes + Casual plasma glucose   11.1mmol/L （ 200mg/dl) or  Fasting plasma glucose （ FPG ）   7.0mmol/L （ 126mg/dl ） or  2h-Post load plasma glucose(2h-PG)   11.1mmol/L （ 200mg/dl ）  If positive, confirm diagnosis with 7days

8. Symptoms  thirst  polyuria  polyphagia  unexplained weight loss  weakness (fatigue)

9. Criteria for the diagnosis of DM mmol/L (mg/dl) Normal Impaired Fasting Glucose (IFG) Impaired Glucose Tolerance (IGT) Diabetes Mellitus (DM) Fasting plasma glucose (FPG)  6.1  6.1 and  7.0 --  7.0 2-Hour postload glucose (2-hPG)  7.8 --  7.8 and  11.1  11.1 Random plasma glucose --  11.1 with symptoms

10. Laboratory Findings 1.Blood glucose (FPG and 2-hPG) 2.Urinary glucose 3.Urinary ketone 4.HbA1c and FA (fructosamine) 5.OGTT 6.Insulin / CP releasing test 7.Others (Blood lipid/ UAER/ Immune markers (anti-GAD,ICA,IAA)

11. Coates PA et al. Diabetes Res Clin Pract 1994;26:177 FPG 8-12 mmol/L FPG 12–15 mmol/L FPG < 8 mmol/L FPG > 18 mmol/L normal T2DM 0.40 1.00 0.80 0.60 insulin 0.20 0 –300306090120150180210240 time (min) nmol/L Insulin releasing test

12. Outline 1. Definition 2. Diagnosis 3. Classification 4. Complications 5. Management

13. 3. Classification (1999WHO) Type1 diabetes (T1DM)  Type1 diabetes (T1DM) Immune mediated Idiopathic Type 2 diabetes (T2DM)  Type 2 diabetes (T2DM)  Other specific types Genetic defects of  -cell function Genetic defects of insulin action Disease of the exocrine pancreas Endocrinopathies Drug - or chemical-induced Infections Anti-insulin receptor antibodies Other genetic syndromes sometimes associated with diabetes Gestational diabetes mellitus (GDM)  Gestational diabetes mellitus (GDM)

14. 3.1 Type 1 diabetes  β-cell destruction, usually leading to absolute deficiency 1. Immune-mediated diabetes (Type1A) Latent autoimmune diabetes in adults, LADA 2. Idiopathic diabetes (Type1B)

15. Autoantibodies  islet cell autoantibody (ICA)  autoantibody to insulin (IAA)  autoantibody to glutamic acid decarboxylase (GADA)  autoantibody to tyrosine phosphatases(IA-2 / IA-2  ) Which reflects the autoimmune processes that have led to  -cell destruction

16. Type 1 DM  Generally <25 years  Rapid onset  Moderate to severe symptoms  Significant weight loss or lean  Ketonuria or keto-acidosis  Low fasting or post-prandial C-peptide  Immune markers (ICA,GADA, IA-2)

17. 3.2 Type 2 diabetes  Heterogeneous diseases  The most common form of diabetes  Disorders of insulin action and insulin secretion  Specific etiology is not known

18. IR – a reduced response of target tissues to circulating insulin Glucose Defective insulin secretion Excessive fatty acid release Reduced glucose uptake Excessive glucose production Carbohydrate Resistance to the action of insulin Insulin

19. 3.2.2  -cell dysfunction  Reduced ability of  -cells to secrete insulin  Impaired ability of  -cells to compensate for IR  Genetic and environmental pathophysiology

20. Features of Type 2 DM  Generally ＞ 40 years  Slowly onset  Not severe symptoms  Obese  Ketoacidosis seldom occur  Nonketotic hyperosmolar syndrome  Normal or elevated C-peptide levels  Genetic predisposition

21. 3.3 Other specific types of diabetes Due to other causes, e.g:   genetic defects of  -cell function (MODY)  genetic defects of insulin action  disease of the exocrine pancreas  endocrinopathies  drug or chemical induced  others

22. 3.4 Gestational diabetes mellitus (GDM)  GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy  6 weeks or more after delivery the woman should be reclassified

23. Course of disease 1.Normal glucose tolerance (NGT) 2.Impaired glucose homeostasis (IGH) 3. Diabetes mellitus (DM)  Impaired fasting glucose (IFG)  Impaired glucose tolerance (IGT)

24. Clinical stages Normoglycemia Normal glucose tolerance Hyperglycemia Impaired glucose regulation IGT / IFG Diabetes mellitus Not insulin requiring Insulin requiring for control Insulin requiring for survival Stages Types Type 1 Type 2 Other Specific Types GDM

25. Diabetes Mellitus Zhao XiaoJuan Department of Endocrinology The First Hospital of China Medical University 2007.11.1

26. Outline 1. Definition 2. Diagnosis 3. Classification 4. Complications 5. Management

27. 4. Chronic Complications Diabetic retinopathy Diabetic nephropathy Cardiovascular disease Stroke Diabetic neuropathy Peripheral vascular disease Diabetic foot macrovascular microvascular

28. DM: Impact on patient  Blindness 10%  Loss of reading vision 15%  Amputation 12%  End stage kidney failure 30%  Myocardial infarction  2-4  Excess mortality  2-8

29. Others  Hypertension  Abnormalities of lipoprotein metabolism  Periodontal disease

30. Metabolic syndrome  Abdominal obesity  IGR or DM  Hypertension  Increased triglycerides  Decreased HDL cholesterol  Microalbuminuria

31. Acute Complications Acute, life-threatening consequences:  Hyperglycemia with ketoacidosis  Nonketotic hyperosmolar syndrome

32. Complications complications MacrovascularMicrovascular acute chronic Infection DKA NHDC CerebrovascularCardiovascular Peripheral Vascular NephropathyRetinopathyNeuropathy

33. Diagnosis procedure symptoms clues &risk factors FPG / 2h-PG equivocal raised values under criteria except DM OGTT NGT IFG/IGT DM classifications complications

34. Outline 1. Definition 2. Diagnosis 3. Classification 4. Complications 5. Management

35. 1.Education 2.Food planning 3.Physical activity 4.Pharmacological treatment 5.Monitoring

36. 5. 1Education of DM It is important that all diabetics are educated in self regulation:  The nature of the disorder  Risk of complications.  Individual targets of treatment  food intake, physical activity and drugs  Self-monitoring of blood or urine glucose  How to cope with emergencies such as hypoglycemia

37. 5.2 Monitoring  Blood glucose levels - before each meal - at bedtime  Urine glucose testing  Urine ketone tests (should be performed during illness or when blood glucose is  11.1mmol/L )

38. 5.3 Food Planning  Weight control  50-60%of the total dietary energy should come from complex carbohydrates  20-25% from fats and oils  15-20% from protein  Restrict alcohol intake  Restrict salt intake to below 7g/d

39. 5.4 Physical Activity  Physical activity play an important role Help weight reduction Help weight reduction Improving insulin sensitivity Improving insulin sensitivity Improving glyceamic control Improving glyceamic control

40. 5.4 Physical Activity  Do sparingly: avoid sedentary activities  Do regularly: participate in leisure activities and recreational sports  Do every day: adopt healthy lifestyle habits

41. 5.5 pharmacological therapy

42. 5.5.1 Insulin  Indication  Preparation  Therapy  Adverse reaction

43. 5.5.1.1 Indications of insulin  T1DM&GDM  T2DM Acute metabolic disturbance :NHDC /DKA Pregnancy and lactation surgery Severe diabetics

44. 5.5.1.2 Insulin Preparations 5.5.1.2 Insulin Preparations Preparations HumanAnaloguesAnimal Ultra-shortLisproaspart Short Novolin R Humulin R R I semilente Intermediate Novolin N Humulin N NPHLente Long Novolin UL Humulin UL PZIUltralente Ultra-longGlargineDetemir Mixture Novolin 30R Novolin 50R Humulin 70/30

45. Time actions of various types of insulin TypeOnset of action Peak effect Duration of action Ultra short-acting 1 Short-acting 0.52-46-8 Intermediate-acting 2-48-1218-24 Long-acting 5-716-1830-36 Ultra long-acting 1-2-24 Insulin mixtures Variableactions page 981 table 7-24-9

46. Rapid Acting Insulin Analogues  Insulin Aspart -Asp(B28)-Insulin  Insulin Lispro -Lys(B28),Pro(B29)-Insulin

47. Long Acting Insulin Analogues  Insulin Glargine -Glycine(A21)+2 arginine(B30)  Insulin Detemir

48. 5.5.1.3 Insulin Therapy BreakfasLunchDinnerSleep 1 RI 2 RI+/-NPH+/- RIRI+/- NPH 3 RI NPH 4 RI+ULRI 5 RI+ULRIRI+UL 6 RI UL

49. 4:0016:0020:0024:004:00 BreakfastLunchDinner Ideal Basal/Bolus Insulin Absorption Pattern 8:00 12:008:00 Time Plasma Insulin

50. Aspart – adding an additional injection

51. Continuous Subcutaneous Insulin Infusion ( CSII)

52. 5.5.1.4 Problems associated with insulin  Hypoglycemia reaction  Insulin resistance  Somogyi phenomenon  Osmotic lens change (visual blurring)  Insulin edema

53. 5.5.2 Oral anti-diabetic (OAD) agents 5.5.2 Oral anti-diabetic (OAD) agents 1.Sulphonylureas 2. Biguanides 3.  -Glucosidase inhibitors 4. Thiazolidinediones 5. Glinides 6. Other

54. 5.5.2.1 SU insulin secretagogue  Main action is the stimulation of insulin secretion from the pancreatic  -cells  The first-line drug in type 2 diabetes patients who are not very obese  Main adverse reaction is hypoglycemia

55. 5.5.2.2Biguanides insulin sensitizer  Increases insulin sensitivity  Reduced hepatic glucose production  First-line therapy in the obese  Without weight gain and hypoglycemia.  Adverse reactions are gastrointestinal intolerance and lactic acidosis

56. 5.5.2.3  -Glucosidase inhibitors  Decrease post-prandial hyperglycemia  Have weight-reducing effect.  First-line therapy with diet, or in combination with SU, biguanides and insulin.  Do not cause hypoglycemia

57. 5.5.2.4 Thiazolidinediones (TZD)  Reduce insulin resistance  Do not enhance insulin production.  Do not cause hypoglycemia.  Conjunction with other antiglycemic agents

58. 5.5.2.5 Glinides  A new generation of SU-like agents  Stimulate first-phase insulin secretion  May be used as monotherapy  Combination with biguanides or thiazolidinediones

59. 5.5.2.6 Others  Lipaglutide (GLP-1 Analogues)

60. Drug Treatment in Type 2 Diabetes Pancreas Liver Muscle Impaired insulin secretion Reduced muscle glucose uptake TZD Metformin TZD Metformin SulphonylureaGlinides Increased hepatic glucose production Glucosidase inhibitors Metformin Hyperglycemia _ stomach intestine

61. Combination therapy  small doses of each drug  avoid the individual side-effects of each agent

62. Combination therapy in T2DM SulphonylureasGlinides Glucosidase inhibitors  - Glucosidase inhibitors BiguanidesThiazolidinediones insulin

63. OAD + basal insulin OAD + multiple daily insulin injections OAD monotherapy OAD combinations OADs uptitration 7 6 9 8 10 Duration of diabetes A1C = 7% OAD = oral anti-diabetic A1C = 6.5% Adapted from Del Prato S, et al. Int J Clin Pract 2005; 59:1345-55. A1C (%) Treatment to Target: Aggressive Management of Glycemic Control

64. ADA 2007 intensive insuln + SU + TZD + basal insuln intensive insuln or basal insuln  metformin  TZD* healthy lifestyle + metformin + basalinsuln+ SU + TZD HbA 1C > 7% lifestyle + metformin + basal insuln Diabetes Care 2007 ； 30 （ SUPPLEMENT 1 ）

65. The Aims of Treatment  Relief of hyperglycemic symptoms  Avoidance of acute metabolic disturbance  Prevent or delay the onset of the long-term complications  In children normal growth and development

66. OptimalFairPoor Plasma glucose (mmol/L) FPG 2-hPG 4.4-6.1 4.4-8.0  7.0  10.0 >7.0 >10.0 HbA1c(%) < 6.5<6. 5-7.5>7.5 Blood pressure (mmHg) <130/80 >130/80- <140/90 >140/90 BMI (kg/m 2 ) Male female <25 <24 <27 <26  27  26 Total cholesterol(mmol/L) <4.5  4.5  6.0 HDL- cholesterol(mmol/L) >1.11.1-0.9<0.9 Triglycerides(mmol/L) <1.5<2.2  2.2 LDL- cholesterol(mmol/L) <3.02.5-4.0>4.0 Targets for control

67. WHO. Available at: www.who.int/diabetes/facts/world_figures/en/. Last accessed: January 2005. Worldwide prevalence of diabetes in 2030 (projected)

68. Thank you