Diabetes Mellitus in pregnancy " Gestational diabetes mellitus''
Diabetes mellitus - IMBM · Diabetes Mellitus 52 Incretins •GLP-1 & GIP •“Incretins” are...
Transcript of Diabetes mellitus - IMBM · Diabetes Mellitus 52 Incretins •GLP-1 & GIP •“Incretins” are...
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
4Diabetes 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
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
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DM type 2 and obesity
Diabetes Mellitus
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DM type 2 and obesity
Diabetes Mellitus
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DM type 2 and genetics
Diabetes Mellitus
14Diabetes 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
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Pathogenesis of DM type 2
Diabetes Mellitus
18Diabetes Mellitus
Basics
• Gestational DM
– Placental hormones
19Diabetes Mellitus
Basics
• Gestational DM
– Placental hormones
• Other specific types of DM
– Neonatal Diabetes Mellitus – monogenic • Age <6 months – mutations KCJN11
– Maturity Onset Diabetes of the Young – monogenic
• MODY 1-11 – mutations of HNF, glucokinase, insulin
– Maternally inherited diabetes and deafness – monogenic
• MIDD – mtDNA
– Latent Autoimmune Diabetes of the Adults
• LADA (cca. 5-10% DM 2), type 1,5
– Secondary and Iatrogenic DM
• Hormones, immunosuppressives, streptozotocin, aloxan
– Impaired/Increased Fasting Glucose (IFG)
– Impaired Glucose Tolerance (IGT)
20Diabetes 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
29Diabetes 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
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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
49Diabetes Mellitus
Glucose uptake
Control DM 2
Brain
Muscle
Adipose
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Splachnic
50Diabetes Mellitus
51Diabetes Mellitus
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DG
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DIn
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oral
intravenous
Insulin secretion
after oral and intravenous glucose application
Inkretins
52Diabetes Mellitus
Incretins
• GLP-1 & GIP
• “Incretins” are secreted by jejunum and ileum as a response to food intake
• Stimulate the secretion of insulin
• Decrease the secretion of glucagon
• Slow-down gastric emptying
• Increase satiety
• Improve insulin sensitivity
• Increase the number of beta cells and improve their functions
53Diabetes Mellitus
Absorbed nutrition
Neural signals
Endocrine signals
GUT PANCREAS
Enteroinsular axis
54Diabetes Mellitus
Incretin drugs
• Analogues of GLP-1
– Exenatide
– Liraglutide
• Inhibitors of dipeptidyl peptidase 4 (DPP4)
– Vildagliptin
– Sitagliptin
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Metabolic surgery
Diabetes Mellitus
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Metabolic surgery
Diabetes Mellitus
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Metabolic surgery
Diabetes Mellitus
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Combinatory drugs
Diabetes Mellitus
60Diabetes Mellitus
61Diabetes Mellitus
Inositol-3-phosphate
62Diabetes Mellitus
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SGLT2 inhibitors
Diabetes Mellitus
64Diabetes Mellitus
67Diabetes Mellitus
Resistin
68Diabetes Mellitus
Klotho
69Diabetes Mellitus
70Diabetes Mellitus
Basics
• Pathogenesis of DM complications
– Ketones
– Sorbitol
– Advanced glycation end products (AGEs)
– Reactive oxygen species (ROS)
71Diabetes Mellitus
Basics
72Diabetes Mellitus
Basics
73Diabetes Mellitus
Carbonyl stress
• Advanced glycation end products (AGEs)
74Diabetes Mellitus
Carbonyl stress
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Carbonyl stress
Diabetes Mellitus
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Oxidative stress
Diabetes Mellitus
77Diabetes 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
78Diabetes 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
79Diabetes 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
80Diabetes Mellitus
• Diagnostika
81Diabetes Mellitus
• Diagnostika
82Diabetes 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
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Secondary prevention
Diabetes Mellitus
84Diabetes Mellitus
85Diabetes Mellitus
Treatment of DM
86Diabetes Mellitus
Treatment of DM
87Diabetes Mellitus
Treatment of DM
88Diabetes Mellitus
Treatment of DM
89Diabetes Mellitus
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Primary prevention?
Diabetes Mellitus
92Diabetes Mellitus