diabetes mellitus - imbm · –ifg, igt, mody, lada. 4 basics diabetes mellitus. diabetes mellitus...
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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
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
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
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
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)
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
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...)
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
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
38Diabetes Mellitus
Insulin physiology
• Contraregulation
– Glucagon
– Cortisol
– Adrenalin
– Somatotropin
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
69Diabetes Mellitus
Basics
• Pathogenesis of DM complications
– Ketones
– Sorbitol
– Advanced glycation end products (AGEs)
– Reactive oxygen species (ROS)
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
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