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
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2. Diabetes mellitus - 1 Definition The scope of the problem
Glucose homeostasis
Mechanism of insulin action
Insulin and its antagonists
(repetition of physiology and biochemistry)
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3. 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
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4. 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
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5. 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.
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6.
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7. Diabetes: A global emergency
Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years)

8. Diabetes: A global emergency
Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years)
vs Eu ; 58-67
Afr ; 16-41
WORD ;
WHY? DG
AGE
OBESITY

9. 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
Incidence 7900, rising by 3% yearly
WHY?
I DON’T NOW

10. 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
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11. Symptoms of diabetes mellitus
NOTHING
Type 2 for long time (months, years)
Hypertension
Myocardial infarction, stroke with very bad prognosis
Microangiopathic complications (amputation)
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12. Symptoms of diabetes mellitus
NOTHING
Gestational diabetes mellitus
Screening!
Harmful both for baby and mother
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13. Symptoms of diabetes mellitus
Think of it
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14. 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
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15. 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.
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16. Two types of diabetes ? Bornstein & Lawrence, 1951 AGE SEX 32 m 52 f 928 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 ?
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17. 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 ?
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18. 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?
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19. 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
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20. 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
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21. 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
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22. IR
glucose
GLUT4
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23. INSULIN
glucose IR
GLUT4
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24. INSULIN
glucose IR
GLUT4
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25. 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
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26. GLUT2 MIT GK K+ Ca ++ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018 22.5.2019
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Ca ++

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

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

29. GLUT2 MIT GK ATP K+ Ca ++ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018
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Ca ++ 29

30. GLUT2 MIT GK ATP Ca ++ K+ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018
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31. GLUT2 MIT GK ATP Ca ++ K+ GLUCOSE INSULIN SUR1 KIR 6.2 18.3.2018
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32. 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
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33.
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34. The secretion of insulin
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35. A big gene on 19th chromosome (22 exons) 300 – 400 kDa
transmembrane glycoprotein
4 subunits
3 domains
Very conservative structure
(drosophila)
Tyrosinkinase autophosphorylation,
phosphorylation
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36.
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37.
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38. 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
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39.
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40. 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)
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41. 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!!!
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42. 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)
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