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
16
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
49
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
62Diabetes Mellitus
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