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2Diabetes Mellitus
Level 0
Cell interior
Glucose
InsulinCell
membrane
3Diabetes Mellitus
Level 0
• 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
Level 0
Diabetes Mellitus
5Diabetes Mellitus
Level 0
• 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
Level 0
• 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
Level 0
• 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
Pathogenesis of DM type 2
Environment
Obesity
Genetics
Defect of ß cells
Exhaustion
of ß cellsDM Type 2
Insulin resistance
Relative insulin deficiency
IDDM
Altered secretion
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Pathogenesis of DM type 2
Diabetes Mellitus
17Diabetes Mellitus
Level 0
• Specific types of DM
– 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
– Gestational DM
• Placental hormones
– Secondary and iatrogenic DM
• Hormones, immunosuppressives, streptozotocin, aloxan
– Impaired/Increased Fasting Glucose (IFG)
– Impaired Glucose Tolerance (IGT)
18Diabetes Mellitus
Level 0
• Insulin resistance
– Obesity, DM, „systemic diseases“
– Prereceptor
• Immunity, metabolism, genetics
– Receptor
• Gene, expression, transport, degradation
– Postreceptor
• Downstream pathways, glucose transport, enzymes of
glycolysis
19Diabetes Mellitus
Level 0
• Insulin resistance syndrome
– Reaven’s metabolic syndrome X
– Central obesity
– DM type 2
– Hyperlipidemia
– Hypertension
– Hyperurikemia
– Hyperfibrinogenemia
– Hyperandrogenism
20Diabetes Mellitus
21Diabetes Mellitus
Level 0
• Diabetic nephropathy
– Hyperfunction of glomeruli
– Hyperfiltration
– Mesangioproliferative changes
– Microalbuminuria
– Proteinuria
– Hypertension
– „Nephrectomy“
22Diabetes Mellitus
Blood Urine
Microangiopathy
Nephropathy
Health Microalbuminuria Proteinuria
Blood Urine Blood Urine
23Diabetes Mellitus
Level 0
• 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...)
24Diabetes Mellitus
Level 0
Dizziness
Sweating Irritability
Tremor
•Hypoglycemia
25Diabetes Mellitus
Level 0
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
26Diabetes Mellitus
27Diabetes Mellitus
Level 1
28Diabetes Mellitus
Level 1
29Diabetes Mellitus
Level 1
• In the liver insulin
– Increases glucose uptake
– Stimulates glycogen and
fatty acid synthesis
– Inhibitis synthesis of
ketone bodies from fats
30Diabetes Mellitus
Level 1
• In muscles insulin
– Increases glucose and
amino acid uptake
– Increases glycogen
synthesis
– Stimulates protein
synthesis and inhibits
proteolysis
31Diabetes Mellitus
Level 1
• In fat tissue insulin
– Increases glucose uptake
– Stimulates fatty acid
synthesis
– Inhibits lipolysis
32Diabetes Mellitus
Level 1
33Diabetes Mellitus
Level 1
• Contraregulation
– Glucagon
– Cortisol
– Adrenalin
– Somatotropin
34Diabetes Mellitus
Level 1
• DM
– Endocrine or metabolic diseases???
– Viruses and their role in the pathogenesis of DM
• Enteroviruses (Coxsackie B), rotaviruses, rubella
– Molecular mimicry
• Cow milk antigens (casein)
• Gliadin
• Infections
35Diabetes Mellitus
36Diabetes Mellitus
37Diabetes Mellitus
Symptoms of DM
1. POLYDIPSIA
BLOOD CELLS
BLOOD CELLS
38Diabetes Mellitus
Level 1
2. POLYURIA
39Diabetes Mellitus
Level 1
3. POLYPHAGIA
40Diabetes Mellitus
Level 1
4. LOSS OF WEIGTH
41Diabetes Mellitus
Level 1
5. FATIQUE
42Diabetes Mellitus
43Diabetes Mellitus
Glucose uptake in tissues
Control DM 2
Brain
Muscle
Adipose
7
6
5
4
3
2
1
0
Splachnic
44Diabetes Mellitus
45Diabetes 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
46Diabetes 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
47Diabetes Mellitus
Absorbed nutrition
Neural signals
Endocrine signals
GUT PANCREAS
Enteroinsular axis
48Diabetes Mellitus
Inkretin drugs
• Analogues of GLP-1
– Exenatide
– Liraglutide
• Inhibitors of dipeptidyl peptidase 4 (DPP4)
– Vildagliptin
– Sitagliptin
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Metabolic surgery
Diabetes Mellitus
50
Metabolic surgery
Diabetes Mellitus
51
Metabolic surgery
Diabetes Mellitus
52
Combinatory drugs
Diabetes Mellitus
53Diabetes Mellitus
Inositol-3-phosphate
54Diabetes Mellitus
55
SGLT2 inhibitors
Diabetes Mellitus
56Diabetes Mellitus
57Diabetes Mellitus
58Diabetes Mellitus
59
Heterogenity of DM
Diabetes Mellitus
60Diabetes Mellitus
Resistin
61Diabetes Mellitus
Klotho
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63Diabetes Mellitus
Level 1
• Pathogenesis of DM complications
– Ketones
– Sorbitol
– Advanced glycation end products (AGEs)
– Reactive oxygen species (ROS)
64Diabetes Mellitus
Level 1
65Diabetes Mellitus
Level 1
66Diabetes Mellitus
Level 1
• Advanced glycation end products (AGEs)
67Diabetes Mellitus
Level 1
68
Level 1
Diabetes Mellitus
69
Level 1
Diabetes Mellitus
Mean plasma glucose
A1C (%) mg/dL mmol/L
6 126 7.0
7 154 8.6
8 183 10.2
9 212 11.8
10 240 13.4
11 269 14.9
12 298 16.5
70
Level 1
Diabetes Mellitus
71Diabetes Mellitus
Level 1
• 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
72Diabetes Mellitus
Level 1
• 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
73Diabetes Mellitus
Level 1
• 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
74Diabetes Mellitus
Level 1
• Diagnostics
75Diabetes Mellitus
Level 1
• Diagnostics
76Diabetes Mellitus
Take home message 1
• Insulin is an anabolicum
• Oxidative and carbonyl stress are involved in the
pathogenesis of DM and its complications
• Oral glucose tolerance test (oGTT)
77Diabetes 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
78
Secondary prevention
Diabetes Mellitus
79
Primary prevention?
Diabetes Mellitus
80Diabetes Mellitus
81Diabetes Mellitus
82Diabetes Mellitus
Level 3
83Diabetes Mellitus
Level 3
84Diabetes Mellitus
Level 3
• Pharmacotherapy
– Insulin
• Bovine, porcine
• Human – recombinant
– Peroral antidiabetics
• Sulfonylurea – Glibenclamid, tolbutamid
• Repaglinid - dtto
• Biguanidy – Metformin
• Thiazolidendiony (Insulinsensitizer)
• Acarbose
– Antihypertensives (ACE inhibitors, beta blockers)
85Diabetes Mellitus
Level 3
• DCCT
– 1993 Diabetes Control and Complications Trial
– Intensive insulin therapy
• 60% neuropathy
• 76% retinopathy
• 39% nefropathy
• 53% renal and eye disorders
86Diabetes Mellitus
Level 3
• UKPDS
– 1998 UK Prospective Diabetes Study
• Antihypertensive therapy
• Blood pressure
• Intensive monitoring of glycemia
• 1% HbA1C 25% mortality
87Diabetes Mellitus
Level 3
88Diabetes Mellitus
Level 3
89Diabetes Mellitus
Level 3
90Diabetes Mellitus
Level 3
91Diabetes Mellitus
92Diabetes Mellitus
Level 3
• Gene therapy
– Ex vivo
• Transformation of stem cells
• Cultivation of beta cells
– In vivo
• Naked DNA
• Viral vectors
• Transformed bacteria
93Diabetes Mellitus
Level 3
94Diabetes Mellitus
Level 3
95Diabetes Mellitus
Level 3
96Diabetes Mellitus
Level 3
97Diabetes Mellitus
98Diabetes Mellitus
99Diabetes Mellitus
