Diabetes mellitus - patophysiology

1. Diabetes mellitus - patophysiology

2. Diabetes mellitus (DM) • It is a group of chronic, progressive, etiopathologically different diseases and their connecting typical feature is hyperglycaemia. • DM is caused by absolute or relative insufficiency of insulin secretion. • It is accompanied by complex disorder in metabolisms of carbohydrates, lipids and proteins. Basic terms: Glycaemia Hyperglycaemia Hypoglycaemia

3. Diabetes mellitus (DM) It leads to high risk of morbidity, invalidity and mortality. It belongs to vascular diseases – damage of vascular wall with severe consequences!!!!

4. Cause of death in type diabetes Cardiovascular complications others

5. Physiology of glucoregulation Hormonal • insulin • glucagon, adrenalin, STH, cortisol – antagonists Autoregulation (substrate regulation) β-cells=glucose sensor Nervous infl. – PSY ↓ glu - SY ↑ glu 4 – 8 mmol/l

6. Hormons regulating glycaemia • Pancreas contains 1 million of Langerhans islets. • In each islet - 3 000 of endocrine cells • A cells ….…Glucagon • D cells …….Somatostatin • B cells…...Insulin • PP cells …...Pancreatic polypeptid

7. Discovery of insulin

9. Production of insulin

10. Anatomy of pancreatic islet

11. Hormon circulation in islets

12. Glucose – a main modulator of insulin secretion

13. Modulators of insulin secretion

14. Insulin and its receptora key moment of postreceptor activity is a translocation of glucose transporter GLUT4into the membrane of muscle and adipose cells insulin receptor

15. Glucose homeostasis PLAYERS: • glucose • insulin • insulin receptor • glucose transporter • GLUT1 (ery, CNS, muscles): gly 5 – 7 mmol/l • GLUT2 (liver, kidney, gut, β- cells): 7 – 20mmol/l • GLUT3 (CNS): 1,6mmol/l • GLUT4 (muscles, adipose tissue): 5 mmol/l, transporter concentration is regulated by insulin!!!!!! • GLUT5 (jejunum): fructose absorption

16. Insulin independent – CNS, blood elements, in case of high blood glucose or during physical activity Insulin dependent – muscles, adipose tissue, liver, gut gut glucose liver • gluconeogenesis • glycogenolysis glycolysis glycogenesis

17. glucose IR GLUT4

18. insulin glucose IR GLUT4

19. insulin glucose IR GLUT4

20. insulin glucose α Inzulin receptor tyrozinkinase β insulin receptor substrate 1 - 3 GLUT 4 mitogen activating proteinkinase PI-3-kinase glycogesynthesis lipogenesis proteosynthesis growing activity genes expresion METABOLIC ACTIVITY Insulin function

21. Function of insulin Liver : ↓ gluconeogenesis ↑ protein synthesis ↓ glycogenolysis ↓ FFA oxidation Muscle: ↑ absorption and glucose oxidation ↑ glycogen synthesis Adipose tissue : ↓ lipolysis and release of FFA Beta cells of pancreas, endothelial cells, …

22. Physiological insulin production 20 - 40 units per day Basal secretion Suppresses glucose production between meals and overnight Nearly constant levels, pulsatile production (5 – 15 min interval) 50% of daily needs Bolus secretion (Mealtime or Prandial) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour 10% to 20% of total daily insulin requirement at each meal 6-20

23. Endogenous – physiological insulin secretion Endogenous secretion Prandial secetion Baal secretion Insulinemia B L D Time B, breakfast; L, lunch; D, dinner; HS, bedtime. Adapted from: 1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002. 2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.

25. Prandial insulin secretion • According to regulatory mechanism Cephalic phase - CNS Gastrointestinal phase – enlargement of gastric wall and proximal parts of intestinum Substrates phase – nutrients (glycaemia!) • According to type of secretion in time • Early phase: 30 minutes - stored insulin in granules • Late phase: newly produced insulin, last as hyperglycaemia occurs • In 120 min. period after meal, hyperglycaemia should be normalized.

26. glucose IGT/diabetes Healthy indiv. Early phase late phase of insulin secretion Insulin response

28. Classification of DMADA 1997, IDF 1999

29. Symptoms • polyuria • polydipsia • weight lost • dehydratation • acidosis • infections

30. Diagnosis A: DM 1. Symptoms + random glycaemia ≥ 11,1mmol/l 2. Fasting plasma glucose ≥ 7,0 mmol/l 3. Glycaemia in 120. min of OGTT ≥ 11,1mmol/l B: Borderline disorder of glucose homeostasis IFG – fasting plasma glucose 5,6 – 6,9 mmol/l IGT - glycaemia in 120. min of OGTT 7,8 -11,01mmol/l

31. Autoimmune type 1 DM -autoimmune B-cell loss in genetic predisposition - circulating antibodies: - islet-cell autoantibodies (ICA) - insulin autoantibodies (IAA) - glutamic acid decarboxylase antibodies (GAD) = insulitis, main mediators – T-lymfocytes - LADA - latent autoimmune diabetes of adults

32. Type 1 DM - phases • Genetic predisposition • Trigger mechanism • Autoimmune process • Decrease of insulin secretion • Hyperglycaemia, residual insulin secretion = diagnosed DM • Complete lost of insulin secretion

33. Development of B-cells failure Genetic predisposition Immune disorder Normal insulin release Progressive impairment of insulin release 100 50 Total amount of b-cells (%) diabetes „Honeymoon“ phase  birth Time (years)

34. Treatment of DM type 1 : Absolute insulin replacement therapy!!

35. Diabetes mellitus type 2 • Imbalance between insulin secretion and its function at periphery 2 major disorders: • Insulin resistance • Insulin deficiency (relative)

36. Prevalence of abnormal glucose tolerance

37. Worldwide prevalence of DM (according to WHO)

39. Manifestation of DM Postprandial glycaemia glycemia Fasting glycaemia 7mmol/l Insulin resistance β-cells function Insulin secretion - 20 -10 0 10 20 30 years Nature development of DM

40. Patophysiology of type 2 DM • Insulin resistance • Insufficient suppression of liver production of glucose • quantitative and qualitative disorder in insulin production

41. Insulin resistance • Decrease of insulin response at periphery • ½ genetics (mutation of gene for insulin receptors, for glucose transporters, cells enzymes, IRS-1 etc.) • ½ others (metabolic, hormonal and nervous infl., stress, …) • Disorder in efficacy of insulin • Normal plasmatic insulin level causes decreased biological response in organism

42. Disorder in balance: IR/IS Insulin („transfer capacity“) Glucose („size of baggage“)

43. IR → compensatory hyperinsulinemia

44. IR → decrease of insulin secretion

46. Function of insulin Liver : ↓ gluconeogenesis ↑ protein synthesis ↓ glycogenolysis ↓ FFA oxidation Muscle: ↑absorption and glucose oxidation ↑ glycogen synthesis Adipose tissue : ↓ lipolysis and release of FFA Beta cells of pancreas, endothelial cells, …

47. Insulin resistance Liver: ↑ glucose production in liver (glycogenolysis and gluconeogenesis) ++ Muscle: ↓ glucose utilization +++ Adipose tissue: ↑lipolysis, ↑ FFA +

48. Insufficient activity of insulin leads to disorder in metabolism of : • carbohydrates – hyperglycaemia • lipids – lipolysis, ↑ TG, ↑ FFA, ↓ HDL • proteins – proteolysis, protein degradation • minerals – resorption of Na in kidneys, metabolism of Ca

49. Insulin resistance FFA TG VLDL Insulin Insulin inhibits hormon-senzitive lipase physiology FFA TG Insulin

50. Who has a high risk of DM type 2? • Genetically risky individuals • Obese – BMI > 25 • Abdominal obesity: waist circumference > 88cm in women > 102cm in men • Positive FH – relatives with DM2 • IGT, GDM in anamnesis • Hypertension, dyslipidemia, CVD • taking diabetogennous drugs • Ethnics groups