Diabetes mellitus. Diabetes mellitus - 1. Diabetes mellitus Lecture from pathological physiology

Transcription

1 Diabetes mellitus Lecture from pathological physiology Oliver Rácz, Šafárik University, Košice, Slovakia In cooperation with F. Ništiar, (immunology) A. Chmelárová, (biochemistry) D. Kuzmová, B. Jacobs (practical diabetology) and L. Szollár, Semmelweiss University, Budapest Diabetes mellitus - 1 Definition The scope of the problem Glucose homeostasis Mechanism of insulin action Insulin and its antagonists (repetition of physiology and biochemistry) Diabetes mellitus - 2 Symptomatology Classification Diagnostic criteria of diabetic syndromes Etiology and pathogenesis of Type 1 DM Etiology and pathogenesis of Type 2 DM and insulin resistance 1

2 Diabetes mellitus - 3 Acute complications of diabetes and their management Chronic complications of diabetes and their prevention After diagnosis monitoring of compensation MODY, Genetics of T1 and T2DM Perspectives in the treatment of diabetes Twists in the tale of diabetes history Definition of diabetes mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. 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. 2

3 vs Eu 48-58; Afr 7-15; WORD ; WHY? DG AGE OBESITY Symptoms of diabetes mellitus Basic Thirst Polyuria Weight loss Fatigue Other Muscle cramps Obstipation Blurred vision Fungal and bacterial infections If you do not begin insulin therapy immediately nausea, vomitus abdominal pain dehydration Kussmaul breathing (deep, acetone smell) ketones in blood, urine, acidosis COMA DIABETICUM 3

4 Symptoms of diabetes mellitus NOTHING Type 2 for long time (months, years) Hypertension Myocardial infarction, stroke with very bad prognosis Microangiopathic complications (amputation) Symptoms of diabetes mellitus NOTHING Gestational diabetes mellitus Screening! Harmful both for baby and mother Symptoms of diabetes mellitus 4

5 Diagnostic criteria of DM Symptoms of DM and 1 abnormal blood glucose* value fasting 7,0 mmol/l 2h after 75 g glucose or casual 11,1 No symptoms present two abnormal BG values on 2 days (as above) Not a perfect algorhythm Uncertainity of BG assays!!! *Only on laboratory analyzers, from venous plasma; uncertainity 0,5 mmol/l Definition of diabetes mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. 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. Two types of diabetes Bornstein & Lawrence, 1951 AGE SEX 32 m 52 f 9 f 28 m WEIGHT G/ blood 23,9 21,2 22,5 14,9 17,7 16,2 21,2 17,3 17,3 12,9 42 m 35 f 47 f 53 f 46 f 57 m?? G/ urine ketones neg neg neg neg neg insulin ,26 0,29 0,02 0,24 0,20 5

6 Classification of diabetic syndromes Type 1 diabetes mellitus (10 %) autoimmune and idiopathic IDDM, juvenile diabetes Type 2 diabetes mellitus (90 %) NIDDM, adult type Other types of diabetes mellitus (rare, long list) Gestational diabetes mellitus (temporary dg.) And where is LADA and MODY? impaired glucose tolerance and impaired fasting glucose are RISK FACTORS Classification of diabetic syndromes Type 1 diabetes mellitus (10 %?) Type 2 diabetes mellitus (90 %? ) Other types of diabetes mellitus (rare?, long list) Gestational diabetes mellitus (temporary dg.) LADA = late autoimmune diabetes of adults Slow type 1, not very rare, transition between type 1 and 2? Type 1 and 2 are only endpoints of a scale? Classification of diabetic syndromes Type 1 diabetes mellitus (10 %?) Type 2 diabetes mellitus (90 %? ) Other types of diabetes mellitus (rare?, long list) Gestational diabetes mellitus (temporary dg.) MODY = maturity onset diabetes of the young Monogenic forms of diabetes (1 7, mostly AD heredity) Previously classified as T1DM OR T2DM Not very rare 1,5 2 % of patients Good lessons for genes of T2DM And also MITOCHODRIAL DIABETES TRANSIENT NEONATAL DIABETES 6

7 Glucose homeostasis Insulin lowers blood glucose (yes, but...) Insulin enables glucose metabolism in cells (yes, but...) Insulin exerts its effect through insulin receptor a transmembrane protein with kinase activity Key point of postreceptor events (a complicated cascade) is the translocation of glucose transporter GLUT4 to the membrane of muscle and fat cells THE PLAYERS OF THE GAME: GLUCOSE RECEPTOR GLUCOSE TRANSPORTER Cells Hormone AA Mw, kda % A B D PP Glukagon Ch 2 Insulin Amylín Somatostatin Ch 3 Pankreatic polypeptide * glucose IR GLUT4 7

8 glucose IR GLUT4 glucose IR GLUT4 Glucose and insulin secretion GLUT2 glucose transporter of B cells GK glucokinase, glucose sensor of B cells MIT mitochondriae, ATP production ATP sensitive K channel (Kir6.2-SUR1 Potassium inward rectifier channel) Depolarisation Ca influc Insulin secretion diasnew1.ppt 24 8

9 GLUCOSE GLUT2 GK MIT K + SUR1 KIR Ca ++ diasnew1.ppt 25 GLUCOSE GLUT2 GK MIT K + SUR1 KIR Ca ++ diasnew1.ppt 26 GLUCOSE GLUT2 GK MIT K + SUR1 KIR Ca ++ diasnew1.ppt 27 9

10 GLUCOSE GLUT2 GK MIT ATP K + SUR1 KIR 6.2 Ca diasnew1.ppt 28 GLUCOSE GLUT2 GK Ca ++ MIT ATP K + SUR1 KIR diasnew1.ppt 29 GLUCOSE GLUT2 GK Ca ++ MIT ATP K + SUR1 KIR diasnew1.ppt 30 10

11 Glucose and insulin secretion GLUT2 glucose transporter of B cells GK glucokinase, glucose sensor of B cells MIT mitochondriae, ATP production ATP sensitive K channel (Kir6.2-SUR1 Potassium inward rectifier channel) Depolarisation Ca influc Insulin secretion diasnew1.ppt 31 The secretion of insulin 11

12 A big gene on 19 th chromosome (22 exons) kda transmembrane glycoprotein 4 subunits 3 domains Very conservative structure (drosophila) Tyrosinkinase autophosphorylation, phosphorylation 12

13 Time course for insulin action Immediate increase in Gucose uptake into cells (seconds) Changes in enzymatic activity (minutes) Increase in enzyme synthesis: glucokinase, PFK1, pyruvate kinaase (hours to days) glu PFK1 enzyme activity Glucose transporter Changes in gene expression Insulin effects synthesis of glycogen glycolysis synthesis of fatty acids and their esterification synthesis of proteins glycogenolysis and gluconeogenesis oxidation of fatty acids and lipolysis IS ANABOLIC HORMONE The younger sister of a big (10 member) family of growth factors (IGF) 13

14 Insulin effects synthesis of glycogen (liver, fat, muscle) glycolysis (muscle) synthesis of fatty acids and their esterification (L,F) synthesis of proteins (muscle) glycogenolysis and gluconeogenesis (liver) oxidation of fatty acids and lipolysis (fat) ACTS ALSO ON BRAIN AND NERVE CELL FUNCTION!!! Insulin and its antagonists Glucagon glycogen breakdown, gluconeogenesis glycolysis blockade in liver Adrenaline, noradrenaline glycogen breakdown and gluconeogenesis in muscles, lactate glucose in liver Growth hormone (anabolic hormone), lipolysis, proteosynthesis Glucocorticoids gluconeogenesis, block of proteosynthesis Thyroid hormones and oestrogens In physiological conditions synergism (counterregulation) 14