Diabetes mellitus Lecture from pathological physiology © Oliver Rácz, 2007 - 2018 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 18.3.2018 diaen181

Diabetes mellitus - 1 Definition The scope of the problem Glucose homeostasis Mechanism of insulin action Insulin and its antagonists (repetition of physiology and biochemistry) 18.3.2018 diaen181

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 18.3.2018 diaen181

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 18.3.2018 diaen181

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. 18.3.2018 diaen181

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Diabetes: A global emergency Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years)

Diabetes: A global emergency Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years) 2003-25 vs 2017-45 Eu 48-58; 58-67 Afr 7-15; 16-41 WORD 194-333; 425-629 WHY? DG AGE OBESITY

Incidence 7900, rising by 3% yearly Diabetes: A global emergency Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years) Type 1, children < 15 y World 500 000 Incidence 7900, rising by 3% yearly WHY? I DON’T NOW

Symptoms of diabetes mellitus 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 Basic Thirst Polyuria Weight loss Fatigue Other Muscle cramps Obstipation Blurred vision Fungal and bacterial infections diasoce2.ppt

Symptoms of diabetes mellitus NOTHING Type 2 for long time (months, years) Hypertension Myocardial infarction, stroke with very bad prognosis Microangiopathic complications (amputation) diasoce2.ppt

Symptoms of diabetes mellitus NOTHING Gestational diabetes mellitus Screening! Harmful both for baby and mother diasoce2.ppt

Symptoms of diabetes mellitus Think of it diasoce2.ppt

Diagnostic criteria of DM Symptoms of DM and 1 abnormal blood glucose* value fasting ³ 7,0 mmol/l 2h after 75 g glucose or casual ³ 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 diasoce2.ppt

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. diasoce2.ppt

Two types of diabetes ? Bornstein & Lawrence, 1951 AGE SEX 32 m 52 f 9 28 42 35 47 53 46 57 WEIGHT 56 25 41 54 79 69 75 85 83 G/ blood 23,9 21,2 22,5 14,9 17,7 16,2 17,3 12,9 G/ urine +++ ketones + ++ neg insulin 0,26 0,29 0,02 0,24 0,20 ? diasoce2.ppt

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.) impaired glucose tolerance and impaired fasting glucose are RISK FACTORS And where is LADA and MODY ? diasoce2.ppt

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? diasoce2.ppt

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 diasoce2.ppt

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 INSULIN INSULIN RECEPTOR GLUCOSE TRANSPORTER 18.3.2018 diaen181

Pankreatic polypeptide Cells Hormone AA Mw, kDa % A Glukagon Ch 2 29 3500 15-20 B Insulin Amylín 30+21 37 5800 70-80* D Somatostatin Ch 3 14 1500 5-10 PP Pankreatic polypeptide 36 4200 15-25 18.3.2018 dias1801.ppt

IR glucose GLUT4 18.3.2018 diaen181

INSULIN glucose IR GLUT4 18.3.2018 diaen181

INSULIN glucose IR GLUT4 18.3.2018 diaen181

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 22.5.2019 18.3.2018 diasnew1.ppt diaen181 25

GLUT2 MIT GK K+ Ca ++ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018 22.5.2019 diasnew1.ppt diaen181 26 Ca ++

GLUT2 MIT GK K+ Ca ++ GLUCOSE INSULIN SUR1 KIR 6.2 22.5.2019 18.3.2018 diasnew1.ppt diaen181 Ca ++ 27

GLUT2 MIT GK K+ Ca ++ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018 22.5.2019 diasnew1.ppt diaen181 28 Ca ++

GLUT2 MIT GK ATP K+ Ca ++ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018 22.5.2019 diasnew1.ppt diaen181 Ca ++ 29

GLUT2 MIT GK ATP Ca ++ K+ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018 22.5.2019 diasnew1.ppt diaen181 30

GLUT2 MIT GK ATP Ca ++ K+ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018 22.5.2019 diasnew1.ppt diaen181 31

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 22.5.2019 18.3.2018 diasnew1.ppt diaen181 32

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The secretion of insulin 18.3.2018 diaen181

A big gene on 19th chromosome (22 exons) 300 – 400 kDa transmembrane glycoprotein 4 subunits 3 domains Very conservative structure (drosophila) Tyrosinkinase autophosphorylation, phosphorylation 18.3.2018 diaen181

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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 Glucose transporter PFK1 enzyme activity Changes in gene expression 18.3.2018 diaen181

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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   INSULIN IS ANABOLIC HORMONE The younger sister of a big (10 member) family of growth factors (IGF) 18.3.2018 diaen181

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)   INSULIN ACTS ALSO ON BRAIN AND NERVE CELL FUNCTION!!! 18.3.2018 diaen181

Insulin and its antagonists Glucagon – glycogen breakdown, gluconeogenesis glycolysis blockade in liver Adrenaline, noradrenaline – glycogen breakdown and gluconeogenesis in muscles, lactate Þ glucose in liver Growth hormone (anabolic hormone), lipolysis, proteosynthesis Glucocorticoids – gluconeogenesis, block of proteosynthesis Thyroid hormones and oestrogens In physiological conditions synergism (counter-regulation) 18.3.2018 diaen181