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Diabetes mellitus Doc. MUDr. Ing. RNDr. Peter Celec, DrSc., MPH [email protected] www.imbm.sk

Diabetes mellitus - IMBM · –IFG, IGT, MODY, LADA. 4 Basics Diabetes Mellitus. Diabetes Mellitus 5 Basics •Pathogenesis of DM symptoms –Hyperglycemia glycosuria polyuria dehydration

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Diabetes mellitus

Doc. MUDr. Ing. RNDr. Peter Celec, DrSc., MPH

[email protected]

www.imbm.sk

2Diabetes Mellitus

Basics

Cell interior

Glucose

InsulinCell

membrane

3Diabetes Mellitus

Basics

• Definition and classification of DM

– !!!Group of diseases associated with

hyperglycemia!!!

– !!!Disorders of secretion and/or effect of insulin!!!

– Type 1 (ID DM)

– Type 2 (NID DM)

– Gestational DM

– Other secondary types

– IFG, IGT, MODY, LADA

4

Basics

Diabetes Mellitus

5Diabetes Mellitus

Basics

• Pathogenesis of DM symptoms

– Hyperglycemia glycosuria polyuria

dehydration polydipsia

– Tissue starvation loss of muscle and lipid tissue +

loss of minerals and water weight loss despite

increased food intake cachexia

– Mobilization of lipids hyperlipidemia oxidation

of FFA acetylCoA hyperketonemia

ketonuria

6Diabetes Mellitus

Basics

• Etiopathogenesis DM Type I

– ID DM

– Decreased production of insulin

– Genetic and epigenetic factors (50% concordance)

– Autoimmune destruction of beta cells in the pancreas

– Antibodies GAD, ICA, INS

– HLA associations

7Diabetes Mellitus

8

Pathogenesis of DM Type 1

Diabetes Mellitus

9Diabetes Mellitus

Pathogenesis of DM Type 1

Environment

Viruses?

Genetics

HLA-DR3/DR4

Insulin deficiency

Destruction of ß cells

DM type 1

Autoimmune insulitis

10Diabetes Mellitus

Basics

• Etiopathogenesis DM Type 2

– Not NID DM!!!

– Disorders of insulin sensitivity AND! beta cells

– Genetic and epigenetic factors (90% concordance)

– Various hypotheses

– Obesity insulin resistance hyperinsulinemia

down-regulation of receptors glucose toxicity

beta cells disorders

11

DM type 2 and obesity

Diabetes Mellitus

12

DM type 2 and obesity

Diabetes Mellitus

13Diabetes Mellitus

14Diabetes Mellitus

15Diabetes Mellitus

16Diabetes Mellitus

Pathogenesis of DM type 2

Environment

Obesity

Genetics

Defect of ß cells

Exhaustion

of ß cells DM Type 2

Insulin resistance

Relative insulin deficiency

IDDM

Altered secretion

17

Pathogenesis of DM type 2

Diabetes Mellitus

18Diabetes Mellitus

Basics

• Specific types of DM

– Gestational DM

• Placental hormones

– Neonatal Diabetes Mellitus

• Age <6 months – mutations KCJN11

– Maturity Onset Diabetes of the Young

• MODY 1-10 – mutations of HNF, glucokinase, insulin

– Latent Autoimmune Diabetes of the Adults

• LADA (cca. 5-10% DM 2), type 1,5

– Maternally inherited diabetes and deafness

• MIDD – mtDNA

– Secondary and iatrogenic DM

• Hormones, immunosuppressives, streptozotocin, aloxan

– Impaired/Increased Fasting Glucose (IFG)

– Impaired Glucose Tolerance (IGT)

19Diabetes Mellitus

20

Gestational DM

Diabetes Mellitus

21Diabetes Mellitus

Basics

• Insulin resistance

– Obesity, DM, „systemic diseases“

– Prereceptor

• Immunity, metabolism, genetics

– Receptor

• Gene, expression, transport, degradation

– Postreceptor

• Downstream pathways, glucose transport, enzymes of

glycolysis

22Diabetes Mellitus

Basics

• Insulin resistance syndrome

– Reaven’s metabolic syndrome X

– Central obesity

– DM type 2

– Hyperlipidemia

– Hypertension

– Hyperurikemia

– Hyperfibrinogenemia

– Hyperandrogenism

23Diabetes Mellitus

24Diabetes Mellitus

25Diabetes Mellitus

Basics

• Diabetic nephropathy

– Hyperfunction of glomeruli

– Hyperfiltration

– Mesangioproliferative changes

– Microalbuminuria

– Proteinuria

– Hypertension

– „Nephrectomy“

26Diabetes Mellitus

Blood Urine

Microangiopathy

Nephropathy

Health Microalbuminuria Proteinuria

Blood Urine Blood Urine

27Diabetes Mellitus

Basics

• Acute and chronic complications of DM

– Acute – diabetic coma

• 1. Hyperglycemia – diabetic ketoacidosis (DM1)

• 2. Hyperosmolar hyperglycemic state (DM2)

• 3. Severe hypoglycemia (coma)

– Chronic

• 1. Microangiopathy

• 2. Macroangiopathy

• 3. Neuropathy

• (nephropathy, infections, gingivitis, cataract...)

28Diabetes Mellitus

Hypoglycemia

Dizziness

Sweating Irritability

Tremor

29

Hyperglycemia

Diabetes Mellitus

30Diabetes Mellitus

Basics

Hypoglycemic coma Hyperglycemic coma

with ketoacidosis

Hyperglycemic coma

without ketoacidosis

DM 1 or 2 DM 1 DM 2

Glucagon, glucose Insulin, rehydration, K+ Rehydration, insulin, K+

1-3 mmol/l 15-30 mmol/l 30-60 mmol/l

Glycosuria negative Glycosuria positive Glycosuria positive

Sweating, tachycardia Kussmaul, ketone smell Without ketoacidosis

31Diabetes Mellitus

32Diabetes Mellitus

Insulin production

33Diabetes Mellitus

Insulin

34Diabetes Mellitus

Insulin physiology

• In the liver insulin

– Increases glucose uptake

– Stimulates glycogen and

fatty acid synthesis

– Inhibitis synthesis of

ketone bodies from fats

35Diabetes Mellitus

Insulin physiology

• In muscles insulin

– Increases glucose and

amino acid uptake

– Increases glycogen

synthesis

– Stimulates protein

synthesis and inhibits

proteolysis

36Diabetes Mellitus

Insulin physiology

• In fat tissue insulin

– Increases glucose uptake

– Stimulates fatty acid

synthesis

– Inhibits lipolysis

37Diabetes Mellitus

Basics

38Diabetes Mellitus

Insulin physiology

• Contraregulation

– Glucagon

– Cortisol

– Adrenalin

– Somatotropin

39

Etiopathogenesis of DM 1

Diabetes Mellitus

40Diabetes Mellitus

41Diabetes Mellitus

42Diabetes Mellitus

Symptoms of DM

1. POLYDIPSIA

BLOOD CELLS

BLOOD CELLS

43Diabetes Mellitus

Symptoms of DM

2. POLYURIA

44Diabetes Mellitus

Symptoms of DM

3. POLYPHAGIA

45Diabetes Mellitus

Symptoms of DM

4. LOSS OF WEIGTH

46Diabetes Mellitus

Symptoms of DM

5. FATIQUE

47Diabetes Mellitus

48Diabetes Mellitus

Glucose uptake

Control DM 2

Brain

Muscle

Adipose

7

6

5

4

3

2

1

0

Splachnic

49Diabetes Mellitus

50Diabetes Mellitus

-30

-10

10

30

50

70

90

0 15 30 45 60 75 90

TIME (min)

0

50

100

150

200

0 15 30 45 60 75 90

TIME (min)

DG

lycem

ia(m

g/1

00m

l)

DIn

su

lin

em

ia(m

U/L

)

oral

intravenous

Insulin secretion

after oral and intravenous glucose application

Inkretins

51Diabetes Mellitus

GLP-1 & GIP

• Entero-insular axis

• “Incretins” are secreted by jejunum and ileum as a response to food intake

• Stimulate the secretion of insulin

• Decrease the secresion of glucagon

• Slow-down gastric emptying

• Increase satiety

• Improve insulin sensitivity

• Increase the number of beta cells and improve their functions

52Diabetes Mellitus

Absorbed nutrition

Neural signals

Endocrine signals

GUT PANCREAS

Enteroinsular axis

53Diabetes Mellitus

Inkretin drugs

• Analogues of GLP-1

– Exenatide

– Liraglutide

• Inhibitors of dipeptidyl peptidase 4 (DPP4)

– Vildagliptin

– Sitagliptin

54

Metabolic surgery

Diabetes Mellitus

55

Metabolická chirurgia

Diabetes Mellitus

56

Metabolická chirurgia

Diabetes Mellitus

57

Combinatory drugs

Diabetes Mellitus

58Diabetes Mellitus

Inositol-3-phosphate

59Diabetes Mellitus

60

SGLT2 inhibitors

Diabetes Mellitus

61Diabetes Mellitus

62Diabetes Mellitus

♀ ♂

63

Heterogenity of DM

Diabetes Mellitus

64Diabetes Mellitus

Resistin

65Diabetes Mellitus

Klotho

66Diabetes Mellitus

67Diabetes Mellitus

68Diabetes Mellitus

69Diabetes Mellitus

Basics

• Pathogenesis of DM complications

– Ketones

– Sorbitol

– Advanced glycation end products (AGEs)

– Reactive oxygen species (ROS)

70Diabetes Mellitus

Basics

71Diabetes Mellitus

Basics

72Diabetes Mellitus

Carbonyl stress

• Advanced glycation end products (AGEs)

73Diabetes Mellitus

Carbonyl stress

74

Carbonyl stress

Diabetes Mellitus

75

Oxidative stress

Diabetes Mellitus

76Diabetes Mellitus

Basics

• Epidemiology

– 3-5% of the whole population are diagnosed diabetics

– cca. 10%

– 50% in the population > 70y

– Incidence and prevalence rapidly increases

– 10% DM 1

– 90% DM 2

77Diabetes Mellitus

Basics

• Diagnostics

– Criteria

• Fasting glucose >7,0 mmol/l

• Random glucose >11,1 mmol/l + symptoms of DM

• HbA1C>6,5%

• oGTT 2h >11,1 mmol/l

– Further diagnostic parameters

• Glycosuria

• Ketonuria

• C-peptide

78Diabetes Mellitus

Basics

• Impaired/Increased fasting glucose (IFG)

– Fasting Glycemia 5,6-6,9 mmol/l

– Insulin resistance in the liver – early phase

• Impaired glucose tolerance (IGT)

– oGTT 2h 7,8-11,1 mmol/l

– 8x higher risk for DM

– Insulin resistance in the muscles – late phase

• Pre-diabetes

79Diabetes Mellitus

• Diagnostika

80Diabetes Mellitus

• Diagnostika

81Diabetes Mellitus

Genetic

predisposition

Preclinical

state

Normal IGT

Disability

Death

Clinical

disease

NIDDM Disability

Death

Complications

Complications

DM type 2

Primary Secondary Tertiary

prevention prevention prevention

82

Secondary prevention

Diabetes Mellitus

83Diabetes Mellitus

84Diabetes Mellitus

Treatment of DM

85Diabetes Mellitus

Treatment of DM

86Diabetes Mellitus

Treatment of DM

87Diabetes Mellitus

Treatment of DM

88Diabetes Mellitus

89Diabetes Mellitus

90

Primary prevention?

Diabetes Mellitus

91Diabetes Mellitus