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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
Q

Enviromental factors which might lead to T1DM

A
  • Geographical localization
  • Viruses
  • Bovine serum albumin and insulin
  • Toxins
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26
Q

Other etiologic causes of T1DM

A
  • Oxidative/ nitrosative stress
  • Epigenetics
  • DNA methylation
  • Histone deacetylation
  • MicroRNAs
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27
Q

How do viruses trigger the autoimmune destruction of beta- cells?

A
  • Viral epitopes, antigenes
  • Cytolytic infections might “present” sequestred proteins
  • Molecular mimicry
  • Coxsackie P2-C and GAD65
  • Enterovirus VP1 and Tyrosin phosphate IA-2
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28
Q

Viruses in etiology of T1DM

A
  • Mumps
  • Coxsackie A, B
  • Rubeola
  • Cytomegalovirus
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29
Q

Toxins in etiology of T1DM

A
  • Alloxan
  • Stretozotocin
  • Nitrozamin
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30
Q

Does the gut microbiota differ between healthy and T1DM children?

A

Yes

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31
Q

Pathogenesis of T1DM (6)

A
  • 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)
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32
Q

Insulitis: autoimmune mechanism

A
  • 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
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33
Q

Celltypes: Insulitis early stage

A

CD8+ cytotoxic T- cells and macrophages

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34
Q

Celltypes: Insulitis late stage

A

Mature B cells

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35
Q

T1DM Antibody:

Islet cell antibody (ICA)

A
  • Detectable years before overt T1DM

- Present in 60- 80% of newly diagnosed cases of T1DM

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36
Q 
T1DM Antibody:
Insulin autoantibodies (IAA)
A
  • Up to 100% in overt T1DM under age 5

- Up to 20% detecatble in overt T1DM over age 15

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37
Q

T1DM Antibody:

Glutamic acid decarboxylase antibodies (GADA)

A
  • 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.
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38
Q

LADA (Latent autoimmune diabetes in adults) (6)

A
  • 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
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39
Q

LADA, previously known as:

A
  • NIRAD: Non- insulin requiring autoimmun diabetes
  • SPT1D: Slowly progressive T1DM
  • ADA. Autoimmune diabetes in adults
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40
Q

Type 2 DM (7)

A
  • Starts in middle aged patients (> 40 yrs)
  • Starts slowly
  • Insulin resistance
  • Hyperinsulinemia
  • Hypoinsulinemia
  • Ketoacidosis is rare
  • Metabolic syndrome in anamneses
41
Q

Three main etiological factors of T2DM

A
  • Genetic predisposition: polymorphism, allelic variants
  • Insulin resistance: cellular insensibility to insulin
  • Decreased insulin secretion: Insufficient beta- cell function
42
Q

Definition of metabolic syndrome (4)

A
  • 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
Q

Positive family history increases the risk of developing DM by?

A

By 2- 4 fold.

44
Q

Genetic factors to insulin resistance or beta- cell weakness (multigenic) may lead to (2)…

A
  • Decreased acitivity of glycogen synthase kinase

- Abnormality of GLUT- 4 transporter translocation

45
Q

Normoglycemia requires what?

A

increased insulin secretion

46
Q

Insulin resistance in T2DM may cause (5):

A
  • Hyperinsulinaemia
  • Maladaptation of beta- cells (exhaustion of beta cells)
  • Decreased cellular glucose uptake
  • IGT (insulin resistance is present)
47
Q

Mechanism of beta- cell failure in T2DM

A
  • Glucotoxicity- decreased insulin secretion
  • Lipotoxicity
  • Oxidative stress
  • Abnormality of glucose sensor and transporter
  • Early “ageing”, limited regeneration (genetic factor)
  • Dedifferentiation
  • Apoptosis
48
Q

Progression of T2DM

A

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
Q

Metabolic abnormalities in DM (7)

A
  • 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
Q

Mechanism om low intracelluluar glucose

A

Increased gluconeogenesis in the liver (which increase hyperglycaemia).

Gluconeogenesis require aa: skeletal mm catabolism
–> negative N- balance.

51
Q

Effect of exercise on insulin action in diabetes (2)

A
  • Insulin dependent GLUT4 translocation

- GLUT4 synthesis

52
Q

Gestational DM (5)

A
  • 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
Q

Patomechanism of gestational DM

A

Pancreatic function is not sufficient for the increased need.

54
Q

T1DM vs T2DM

A
  • 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
Q

Antibodies that might be present in T2DM

A
  • GADA
  • ICA
  • IA-2
  • ZnT8
56
Q

Symptomes of Diabetic Ketoacidosis

A
  • Acetonic breath
  • Nausea
  • Vomiting
  • ABdominal pain
  • Muscle contractions
  • Hyperventilation
  • Increased HR
  • Low RR
57
Q

Mortality of Diabetic Ketoacidosis

A

5- 10%, up tp 20% in elderly

58
Q

Characteristics Diabetic Ketoacidosis (10)

A
  • 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
Q

Se.glucose in Diabetic Ketoacidosis

A

20- 40 mmol/L

60
Q

Increased lipolysis in Diabetic Ketoacidosis will lead to…

A

FFA –> Ketosis –> Metabolic acidosis –> Kussmaul breathing

61
Q

The severe fluid and electrolyte abnormaloty seen in Diabetic Ketoacidosis will cause what?

A

Coma and death

62
Q

Diabetic Ketoacidosis in children (5)

A
  • 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
Q

Definition of diabetic ketoacidosis in children (3)

A
  • 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
Q

Symptomes of Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome

A
  • Exsiccation (“dehydration”)
  • Dry mouth
  • Increased heart rate
  • Low RR
65
Q

Lethality of Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?

A

30- 50%

66
Q

Se. Glucose in Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?

A

40- 100 mmol/L

67
Q

Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome (5)

A
  • 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
Q

Which factors may initiate Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?

A
  • Acute infection
  • Stroke
  • AMI
  • Pancreatitis
  • Drugs
69
Q

Symptoms of Hypoglycemia

A

Sympato- adrenerg (adrenalin):

  • Tachycardia
  • Sweat
  • Hunger
  • Excitedness
  • Tremor

Neurological:

  • Confusion
  • Cramps
  • Neurological signs
70
Q

Treatment of Hypoglycemia

A
  • GLucose

- GLucagon

71
Q

Se. Glucose in Hypoglycemia

A

<3- 3,5 mmol/L

72
Q

Which may be the causes of developing Hypoglycemia?

A
  • Insulin overdose (iatrogenic)
  • Increased insulin sensitivity (exercise)
  • Not enough food intake
73
Q

How much glucose does the brain utilize?

A

1mg/ kg/ min glucose

74
Q

Mechanism of chronic complications

A
  • 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
Q

Polyol pathway

A

GLUCOSE (aldose- reductase) –> SORBITOL (sorbitol reductase) –> FRUCTOSE; Intermediate product have high osmotic activity which inhibits Na+- K+- ATPase

76
Q

Non- enzymatic glycation

A

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
Q

Increased synthesis of prostaglandins

A

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
Q

Oxidative stress

A

Increases the oxidation of “low density lipoprotein” (LDL) –> acceleration of atherosclerosis.

79
Q

Decreased synthesis of heparan- sulfate- proteoglycan (HS- PG)

A

Negatively charged –> inhibits the crossing of albumin and immunoglobulins on the glomerular basement membrane.

80
Q

Haemostais

A
  • 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
Q

Effect of AGE molecules to the haemostasis

A
  • AGE binds immunoglobulins and faciliate LDL deposition in the subintima
  • AGE catalize reaction of free radicals and increase intima proliferation
82
Q

Normal albuminuria

A

Urine:

<20 microgram/ min, <30 mg/ day

83
Q

Low- grade albuminuria (“microalbuminuria”)

A

Urine:
20- 200 microg/ min
30- 300 mg/ day

84
Q

Macroalbuminuria

A

Urine:
>200 microgram/ min
> 300 mg/ day

85
Q

Low- grad albuminuria is a risk factor for what?

A

Diabetic nephropathy

86
Q

Except Diabetic nephropathy, Low- grade albuminuria may also be risk factor for?

A

Cardiovascular disease

(True for non- diabetics as well).

87
Q

Reduction of albuminuria descreases what?

A

The cardiovascular risk

88
Q

Three factors influencing Macroangiopathy

A
  • Diabetes mellitus
  • Atherosclerosis
  • Hypertension
89
Q

What is the cardiovascular risk in patients with DM compared to non- diabetic?

A

Males: 3,8 fold higher risk
Females: 5,5 fold higher risk

90
Q

What are the leading causes of death in patients with DM based on comorbidity and mortality data?

A

AMI and stroke

91
Q

Percentage of patients with T2DM that will die of AMI or stroke?

A

80%

92
Q

What is the mortality of ischaemic heart disease in patients with T1DM?

A

35%

93
Q

What is the diabetic foot?

A

The classical manifestation of late complications.

94
Q

Approach in order to prevent complications?

A
  • Body weight control
  • RR
  • Se. lipids
  • Patient most stop smoking
  • Decrease amount of alcohol intake
  • Careful, regular exercise
  • Optimal diet
95
Q

Treatment of DM?

A
  • SMBG (self- monitoring blood glucose)
  • Insulin treatment
  • Regular HbA1c measurement
  • Education, follow up
  • Lifestyle changes
96
Q

What can be reduced by strict control of glucose level?

A

Both cardiovascular risk and late complications.

97
Q

By simply replacing insulin will be enough to eliminate disease progression?

A

No.

98
Q

IGT and IFG will in long term lead to?

A

MI and stroke

Pathophysiology (14 decks)

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