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Pathophysiology > W.8: Type 1 and 2 Diabetes mellitus > Flashcards

W.8: Type 1 and 2 Diabetes mellitus Flashcards

1
Q

Definition of Diabetes mellitus

A

A group of metabolic diseases characterized by high glucose levels, that result from defects in insulin secretion, or action, or both.

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2
Q

Diabetes mellitus is the number one cause of (3)?

A
  • Chronic renal failure
  • Blindness in adult
  • Leg amputation (non- traumatic)
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3
Q

Acute complications of DM (4)

A
  • Ketoacidotic coma
  • Hyperosmolar hyperglycemic non- ketoacidotic syndrome
  • Lactate- acidoses
  • Hypoglycemia
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4
Q

Chronic complications DM (4)

A
  • Microangiopathia (retino-, nephro-, neuropathy)
  • Macroangiopathia (atherosclerosis, hypertension)
  • Neuropathia (sensory- motor, autonomous)
  • Increased risk of infections
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5
Q

Prevalence of DM (in Hungary)

  • type 1
  • type 2
A

5- 5,5% (0,5 M hungarians)

  • type 1: 5- 10%
  • type 2: 90%
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6
Q

IGT in EU states

A

2,2,- 8,6%

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7
Q

IGT + DM (in Hungary)

A

1- 1,5 M hungarians

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8
Q

Definition type 1 DM

A

Results from body´s failure to produce insulin due to beta- cell destruction

LADA (Latent autoimmune diabetes in adults)

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9
Q

Definition type 2 DM

A

Results from insulin resistance sometimes combined with an absolute insulin deficiency

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10
Q

Definition Gestational DM

A

Pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy.

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11
Q

Genetic defect of beta- cell function

A

MODY 1-6: Maturity onset diabetes of the young.

Monogenic: HNF1A, GCK, HNF4A, IPF1, HNF1B, NEUROD1

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12
Q

Rabson- Mendenhall syndrome

A

Genetic defects in insulin processing or insulin action.

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13
Q

Exocrine pancreas defects

A

Inflammation, trauma, malignancy, cystic fibrosis

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14
Q

Endocrinopathies as underlying cause of dev. of DM (4)

A
  • Acromegaly
  • Cushing synd.
  • Hyperthyreosis
  • Phaeochromocytoma
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15
Q

Drugs as underlying causes of dev. of DM (5)

A
  • Pentamidin
  • Nicotinacid
  • Glucocortociods
  • Thiazids
  • beta- adrenerg agonist
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16
Q

Infections that may lead to dev. of DM (2)

A
  • Coxsackie virus

- Cytomegalovirus

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17
Q

Genetic abnormalites associated with DM (6)

A
  • Down synd.
  • Turner synd.
  • Klinefeter syn.
  • Huntington chorea
  • Porphyria
  • Myotonic dystrophy
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18
Q

Further classification of type 1 DM

A
  • type 1 automimmune DM (type 1A)

- type 1 idiopathic DM (type 1B)

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19
Q

Type 1 idiopathic DM (type 1B)

A
  • Rare, inherited form
  • No autoimmun mechanism
  • Variable need for insulin
  • Asian, african individuals
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20
Q

Type 1 automimmune DM (type 1A) (7)

A
  • Patients under age of 30 (but might develop at any age)
  • Children < 6 years are in high risk
  • Represents 5- 10% of all cases of DM
  • Starts rapidly
  • beta- cell destruction which leads to lack of insulin
  • Autoimmune mechanism
  • Insulin treatment
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21
Q

Type 1 automimmune DM (type 1A) will without insulin treatment lead to?

A
  • Ketoacidoses
  • Coma
  • Death
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22
Q

Classical symptoms of T1DM (4)

A
  • Polyuria, frequent urination: Osmotic diuresis
  • Polydypsia, increased thirst: Consequence of polyuria
  • Polyphagia, increased hunger: Weight loss result
  • Ketoacidoses: in severe cases.
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23
Q

Total mass of 1 million islet cells?

A

1- 1,5 g.

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24
Q

Genetic factors as underlying cause of dev. of T1DM?

A
  • HLA genes

- Non- HLA genes

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25
Enviromental factors which might lead to T1DM
- Geographical localization - Viruses - Bovine serum albumin and insulin - Toxins
26
Other etiologic causes of T1DM
- Oxidative/ nitrosative stress - Epigenetics * DNA methylation * Histone deacetylation * MicroRNAs
27
How do viruses trigger the autoimmune destruction of beta- cells?
- Viral epitopes, antigenes - Cytolytic infections might "present" sequestred proteins - Molecular mimicry * Coxsackie P2-C and GAD65 * Enterovirus VP1 and Tyrosin phosphate IA-2
28
Viruses in etiology of T1DM
- Mumps - Coxsackie A, B - Rubeola - Cytomegalovirus
29
Toxins in etiology of T1DM
- Alloxan - Stretozotocin - Nitrozamin
30
Does the gut microbiota differ between healthy and T1DM children?
Yes
31
Pathogenesis of T1DM (6)
- Genetic predisposition - Trigger (virus, toxin) - Insulitis - Autoimmune reaction - beta- cell destruction (cytotoxic T cells and specific antibodies) - Clinical manifestation (80- 90% destruction of beta- cells)
32
Insulitis: autoimmune mechanism
- exclusice beta- cell damage (A, D, PP cells are intact) - Infiltration of islets and the proliferation of immune cells: Autoreactive CD4+ T- cells: Insulin, GAD, IA-2, ZnT8 - Specific antibodies against beta- cells - Cytokines and chemokines participates in toxicity and the regulation of the process: TNF- alfa, INF- alfa, INF- gamma, CXC chemokin ligand 10
33
Celltypes: Insulitis early stage
CD8+ cytotoxic T- cells and macrophages
34
Celltypes: Insulitis late stage
Mature B cells
35
T1DM Antibody: | Islet cell antibody (ICA)
- Detectable years before overt T1DM | - Present in 60- 80% of newly diagnosed cases of T1DM
36
``` T1DM Antibody: Insulin autoantibodies (IAA) ```
- Up to 100% in overt T1DM under age 5 | - Up to 20% detecatble in overt T1DM over age 15
37
T1DM Antibody: | Glutamic acid decarboxylase antibodies (GADA)
- Detectable in 80% of the patients years before overt T1DM - Several lines of evidence suggest the important role of GADA in the etiology of T1DM. --> It activates T lymphocytes which infiltrate and attack beta- cells and also initiates autoimmune insulitis responsible for the destruction of beta- cells.
38
LADA (Latent autoimmune diabetes in adults) (6)
- T1DM developing in patients > 35 years - Autoantibodies are present (ICA, GADA) - Also called 1,5 type DM - Up 20% of the diagnosed T2DM might be LADA - Initally non- ketotic, non- insulin requiring (diet and oral AD) - Later: Insulin treatment is required
39
LADA, previously known as:
- NIRAD: Non- insulin requiring autoimmun diabetes - SPT1D: Slowly progressive T1DM - ADA. Autoimmune diabetes in adults
40
Type 2 DM (7)
- Starts in middle aged patients (> 40 yrs) - Starts slowly - Insulin resistance - Hyperinsulinemia - Hypoinsulinemia - Ketoacidosis is rare - Metabolic syndrome in anamneses
41
Three main etiological factors of T2DM
- Genetic predisposition: polymorphism, allelic variants - Insulin resistance: cellular insensibility to insulin - Decreased insulin secretion: Insufficient beta- cell function
42
Definition of metabolic syndrome (4)
- Abdominal obesity >102 cm (male) >88 cm (female) - Raised triglycerides >1,7 mmol/L - Reduced HDL cholesterol <1,0 mmol/L (male) <1,3 mmol/L (female) - Raised blood pressure (BP): >130/85 - Insulin resistance; IGF, IGT (DM)
43
Positive family history increases the risk of developing DM by?
By 2- 4 fold.
44
Genetic factors to insulin resistance or beta- cell weakness (multigenic) may lead to (2)...
- Decreased acitivity of glycogen synthase kinase | - Abnormality of GLUT- 4 transporter translocation
45
Normoglycemia requires what?
increased insulin secretion
46
Insulin resistance in T2DM may cause (5):
- Hyperinsulinaemia - Maladaptation of beta- cells (exhaustion of beta cells) - Decreased cellular glucose uptake - IGT (insulin resistance is present)
47
Mechanism of beta- cell failure in T2DM
- Glucotoxicity- decreased insulin secretion - Lipotoxicity - Oxidative stress - Abnormality of glucose sensor and transporter - Early "ageing", limited regeneration (genetic factor) - Dedifferentiation - Apoptosis
48
Progression of T2DM
1) Genetic and environmental factors 2) - Insulin resistance - -> Hyperinsulinemia (beta- cell compensation, fasting glucose normal) - -> IGT (beta- cell decompensation/ exhaustion) 3) Beta- cell mass decrease, dedifferentiation, apoptosis - -> Fasting hyperglycemia - -> Hypoinsulinemia - -> Glucotoxicity
49
Metabolic abnormalities in DM (7)
- Hyperglycemia due to insufficient effect of insulin - Decreased celluluar intake of glucose: hyperglycaemia - Low intracellular glucose - Hyperglycaemia BUT endogen starvation - Energy sourse: FFA from fat tissue - Liver partially metababolise excess FFA - -> Hyperlipidaemia - FA- metabolism is limited within citrate cycle --> excess Acetyl- CoA transforms to Ketone bodies
50
Mechanism om low intracelluluar glucose
Increased gluconeogenesis in the liver (which increase hyperglycaemia). Gluconeogenesis require aa: skeletal mm catabolism --> negative N- balance.
51
Effect of exercise on insulin action in diabetes (2)
- Insulin dependent GLUT4 translocation | - GLUT4 synthesis
52
Gestational DM (5)
- 5-9% of pregnant women - Affect the developing fetus - After giving birth the blood sugar level might normalize - DM develops up to 45% of these patients within 10 yrs - Education and follow up important
53
Patomechanism of gestational DM
Pancreatic function is not sufficient for the increased need.
54
T1DM vs T2DM
- T2DM increasingly affect young patients - T2DM patient MIGHT require insulin DKA might develop in patient with T2DM (stress, severe infection, AMI) - T1DM with excellent metabolic cntrl might become overweight (25%) and insulin resistance can develop
55
Antibodies that might be present in T2DM
- GADA - ICA - IA-2 - ZnT8
56
Symptomes of Diabetic Ketoacidosis
- Acetonic breath - Nausea - Vomiting - ABdominal pain - Muscle contractions - Hyperventilation - Increased HR - Low RR
57
Mortality of Diabetic Ketoacidosis
5- 10%, up tp 20% in elderly
58
Characteristics Diabetic Ketoacidosis (10)
- T1DM, might be seen in T2DM - Acute infection, stress, AMI might initiatie - Lack of insulin - Increased gluoconeogenesis, decreased glucos consumption - Increased lipolysis - Osmotic diuresis due to high Se. glucose - Extra- and intrecellular dehydration - Loss of total, Na+, K+. Mg+ BUT increased Se.K+ due to acidosis - Se.Cl- decreases - Slow development
59
Se.glucose in Diabetic Ketoacidosis
20- 40 mmol/L
60
Increased lipolysis in Diabetic Ketoacidosis will lead to...
FFA --> Ketosis --> Metabolic acidosis --> Kussmaul breathing
61
The severe fluid and electrolyte abnormaloty seen in Diabetic Ketoacidosis will cause what?
Coma and death
62
Diabetic Ketoacidosis in children (5)
- Leading cause of mortality in children with DM1 - RIsh for DKA in children with established T1DM is 1-10%/ year - DKA is the first sign of T1DM in 15- 65% of the children - Children <6 yrs are at especially high risk - DKA first sign of T2DM in 20- 40% of patients
63
Definition of diabetic ketoacidosis in children (3)
- Blood glucose > 11 mmol/L - Metabolic acidosis: venous pH <7,3 or plasma bicarbonate <15 mmol/L - Ketosis, determined by presence of ketones in blood or urine
64
Symptomes of Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome
- Exsiccation ("dehydration") - Dry mouth - Increased heart rate - Low RR
65
Lethality of Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?
30- 50%
66
Se. Glucose in Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?
40- 100 mmol/L
67
Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome (5)
- T"DM, infrequently also in T1DM - Mechanism is not entirely known - Relative lack of insulin. Glucagon is high - Residual insulin is enough for the liver to further metabolise FFA --> prevent synthesis of ketone bodies
68
Which factors may initiate Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?
- Acute infection - Stroke - AMI - Pancreatitis - Drugs
69
Symptoms of Hypoglycemia
Sympato- adrenerg (adrenalin): - Tachycardia - Sweat - Hunger - Excitedness - Tremor Neurological: - Confusion - Cramps - Neurological signs
70
Treatment of Hypoglycemia
- GLucose | - GLucagon
71
Se. Glucose in Hypoglycemia
<3- 3,5 mmol/L
72
Which may be the causes of developing Hypoglycemia?
- Insulin overdose (iatrogenic) - Increased insulin sensitivity (exercise) - Not enough food intake
73
How much glucose does the brain utilize?
1mg/ kg/ min glucose
74
Mechanism of chronic complications
- Polyol pathway - Non- enzymatic glycation - INcreased synthesis of prostaglandins - Oxidative stress - Decreased synthesis of heparan- sulfate- proteoglycan (HS- PG) - Harmostasis - Effect of AGE molecules to the haemostasis
75
Polyol pathway
GLUCOSE (aldose- reductase) --> SORBITOL (sorbitol reductase) --> FRUCTOSE; Intermediate product have high osmotic activity which inhibits Na+- K+- ATPase
76
Non- enzymatic glycation
Glucose + Protein = Schiff base and later Amadori product develops (reversible). If glucose level is high for a long period "advanced glycolisation ednproducts" (AGE) will develop (irreversible). HbA1c measurement
77
Increased synthesis of prostaglandins
Increased amount of diacylglycerol, synthesized from excess glucose, will increase the activity of PKC in capillary endothel of the retina, glomeruli and the heart muscle cells --> Increases the production of TXB2 and PGF.
78
Oxidative stress
Increases the oxidation of "low density lipoprotein" (LDL) --> acceleration of atherosclerosis.
79
Decreased synthesis of heparan- sulfate- proteoglycan (HS- PG)
Negatively charged --> inhibits the crossing of albumin and immunoglobulins on the glomerular basement membrane.
80
Haemostais
- Increased level of plasma fibrinogen (even in IGT) - Decreased level of Protein- C, S and tissue plasminogen activator (tPa) - Alteration of component of the fibrinolysis - Increased synthesis of plasminogen- activator- inhibitor (PAI-1) - Endothel dysfunction leading to increased thrombocyte adhesion and activation
81
Effect of AGE molecules to the haemostasis
- AGE binds immunoglobulins and faciliate LDL deposition in the subintima - AGE catalize reaction of free radicals and increase intima proliferation
82
Normal albuminuria
Urine: | <20 microgram/ min, <30 mg/ day
83
Low- grade albuminuria ("microalbuminuria")
Urine: 20- 200 microg/ min 30- 300 mg/ day
84
Macroalbuminuria
Urine: >200 microgram/ min > 300 mg/ day
85
Low- grad albuminuria is a risk factor for what?
Diabetic nephropathy
86
Except Diabetic nephropathy, Low- grade albuminuria may also be risk factor for?
Cardiovascular disease (True for non- diabetics as well).
87
Reduction of albuminuria descreases what?
The cardiovascular risk
88
Three factors influencing Macroangiopathy
- Diabetes mellitus - Atherosclerosis - Hypertension
89
What is the cardiovascular risk in patients with DM compared to non- diabetic?
Males: 3,8 fold higher risk Females: 5,5 fold higher risk
90
What are the leading causes of death in patients with DM based on comorbidity and mortality data?
AMI and stroke
91
Percentage of patients with T2DM that will die of AMI or stroke?
80%
92
What is the mortality of ischaemic heart disease in patients with T1DM?
35%
93
What is the diabetic foot?
The classical manifestation of late complications.
94
Approach in order to prevent complications?
- Body weight control - RR - Se. lipids - Patient most stop smoking - Decrease amount of alcohol intake - Careful, regular exercise - Optimal diet
95
Treatment of DM?
- SMBG (self- monitoring blood glucose) - Insulin treatment - Regular HbA1c measurement - Education, follow up - Lifestyle changes
96
What can be reduced by strict control of glucose level?
Both cardiovascular risk and late complications.
97
By simply replacing insulin will be enough to eliminate disease progression?
No.
98
IGT and IFG will in long term lead to?
MI and stroke

Pathophysiology (14 decks)

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