W.8: Type 1 and 2 Diabetes mellitus Flashcards
Definition of Diabetes mellitus
A group of metabolic diseases characterized by high glucose levels, that result from defects in insulin secretion, or action, or both.
Diabetes mellitus is the number one cause of (3)?
- Chronic renal failure
- Blindness in adult
- Leg amputation (non- traumatic)
Acute complications of DM (4)
- Ketoacidotic coma
- Hyperosmolar hyperglycemic non- ketoacidotic syndrome
- Lactate- acidoses
- Hypoglycemia
Chronic complications DM (4)
- Microangiopathia (retino-, nephro-, neuropathy)
- Macroangiopathia (atherosclerosis, hypertension)
- Neuropathia (sensory- motor, autonomous)
- Increased risk of infections
Prevalence of DM (in Hungary)
- type 1
- type 2
5- 5,5% (0,5 M hungarians)
- type 1: 5- 10%
- type 2: 90%
IGT in EU states
2,2,- 8,6%
IGT + DM (in Hungary)
1- 1,5 M hungarians
Definition type 1 DM
Results from body´s failure to produce insulin due to beta- cell destruction
LADA (Latent autoimmune diabetes in adults)
Definition type 2 DM
Results from insulin resistance sometimes combined with an absolute insulin deficiency
Definition Gestational DM
Pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy.
Genetic defect of beta- cell function
MODY 1-6: Maturity onset diabetes of the young.
Monogenic: HNF1A, GCK, HNF4A, IPF1, HNF1B, NEUROD1
Rabson- Mendenhall syndrome
Genetic defects in insulin processing or insulin action.
Exocrine pancreas defects
Inflammation, trauma, malignancy, cystic fibrosis
Endocrinopathies as underlying cause of dev. of DM (4)
- Acromegaly
- Cushing synd.
- Hyperthyreosis
- Phaeochromocytoma
Drugs as underlying causes of dev. of DM (5)
- Pentamidin
- Nicotinacid
- Glucocortociods
- Thiazids
- beta- adrenerg agonist
Infections that may lead to dev. of DM (2)
- Coxsackie virus
- Cytomegalovirus
Genetic abnormalites associated with DM (6)
- Down synd.
- Turner synd.
- Klinefeter syn.
- Huntington chorea
- Porphyria
- Myotonic dystrophy
Further classification of type 1 DM
- type 1 automimmune DM (type 1A)
- type 1 idiopathic DM (type 1B)
Type 1 idiopathic DM (type 1B)
- Rare, inherited form
- No autoimmun mechanism
- Variable need for insulin
- Asian, african individuals
Type 1 automimmune DM (type 1A) (7)
- 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
Type 1 automimmune DM (type 1A) will without insulin treatment lead to?
- Ketoacidoses
- Coma
- Death
Classical symptoms of T1DM (4)
- Polyuria, frequent urination: Osmotic diuresis
- Polydypsia, increased thirst: Consequence of polyuria
- Polyphagia, increased hunger: Weight loss result
- Ketoacidoses: in severe cases.
Total mass of 1 million islet cells?
1- 1,5 g.
Genetic factors as underlying cause of dev. of T1DM?
- HLA genes
- Non- HLA genes
Enviromental factors which might lead to T1DM
- Geographical localization
- Viruses
- Bovine serum albumin and insulin
- Toxins
Other etiologic causes of T1DM
- Oxidative/ nitrosative stress
- Epigenetics
- DNA methylation
- Histone deacetylation
- MicroRNAs
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
Viruses in etiology of T1DM
- Mumps
- Coxsackie A, B
- Rubeola
- Cytomegalovirus
Toxins in etiology of T1DM
- Alloxan
- Stretozotocin
- Nitrozamin
Does the gut microbiota differ between healthy and T1DM children?
Yes
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)
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
Celltypes: Insulitis early stage
CD8+ cytotoxic T- cells and macrophages
Celltypes: Insulitis late stage
Mature B cells
T1DM Antibody:
Islet cell antibody (ICA)
- Detectable years before overt T1DM
- Present in 60- 80% of newly diagnosed cases of T1DM
T1DM Antibody: Insulin autoantibodies (IAA)
- Up to 100% in overt T1DM under age 5
- Up to 20% detecatble in overt T1DM over age 15
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.
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
LADA, previously known as:
- NIRAD: Non- insulin requiring autoimmun diabetes
- SPT1D: Slowly progressive T1DM
- ADA. Autoimmune diabetes in adults
Type 2 DM (7)
- Starts in middle aged patients (> 40 yrs)
- Starts slowly
- Insulin resistance
- Hyperinsulinemia
- Hypoinsulinemia
- Ketoacidosis is rare
- Metabolic syndrome in anamneses
Three main etiological factors of T2DM
- Genetic predisposition: polymorphism, allelic variants
- Insulin resistance: cellular insensibility to insulin
- Decreased insulin secretion: Insufficient beta- cell function
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)
Positive family history increases the risk of developing DM by?
By 2- 4 fold.
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
Normoglycemia requires what?
increased insulin secretion
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)
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
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
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
Mechanism om low intracelluluar glucose
Increased gluconeogenesis in the liver (which increase hyperglycaemia).
Gluconeogenesis require aa: skeletal mm catabolism
–> negative N- balance.
Effect of exercise on insulin action in diabetes (2)
- Insulin dependent GLUT4 translocation
- GLUT4 synthesis
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
Patomechanism of gestational DM
Pancreatic function is not sufficient for the increased need.
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
Antibodies that might be present in T2DM
- GADA
- ICA
- IA-2
- ZnT8
Symptomes of Diabetic Ketoacidosis
- Acetonic breath
- Nausea
- Vomiting
- ABdominal pain
- Muscle contractions
- Hyperventilation
- Increased HR
- Low RR
Mortality of Diabetic Ketoacidosis
5- 10%, up tp 20% in elderly
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
Se.glucose in Diabetic Ketoacidosis
20- 40 mmol/L
Increased lipolysis in Diabetic Ketoacidosis will lead to…
FFA –> Ketosis –> Metabolic acidosis –> Kussmaul breathing
The severe fluid and electrolyte abnormaloty seen in Diabetic Ketoacidosis will cause what?
Coma and death
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
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
Symptomes of Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome
- Exsiccation (“dehydration”)
- Dry mouth
- Increased heart rate
- Low RR
Lethality of Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?
30- 50%
Se. Glucose in Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?
40- 100 mmol/L
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
Which factors may initiate Hyperosmolar, hyperglycemic, non- ketoacidotic syndrome?
- Acute infection
- Stroke
- AMI
- Pancreatitis
- Drugs
Symptoms of Hypoglycemia
Sympato- adrenerg (adrenalin):
- Tachycardia
- Sweat
- Hunger
- Excitedness
- Tremor
Neurological:
- Confusion
- Cramps
- Neurological signs
Treatment of Hypoglycemia
- GLucose
- GLucagon
Se. Glucose in Hypoglycemia
<3- 3,5 mmol/L
Which may be the causes of developing Hypoglycemia?
- Insulin overdose (iatrogenic)
- Increased insulin sensitivity (exercise)
- Not enough food intake
How much glucose does the brain utilize?
1mg/ kg/ min glucose
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
Polyol pathway
GLUCOSE (aldose- reductase) –> SORBITOL (sorbitol reductase) –> FRUCTOSE; Intermediate product have high osmotic activity which inhibits Na+- K+- ATPase
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
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.
Oxidative stress
Increases the oxidation of “low density lipoprotein” (LDL) –> acceleration of atherosclerosis.
Decreased synthesis of heparan- sulfate- proteoglycan (HS- PG)
Negatively charged –> inhibits the crossing of albumin and immunoglobulins on the glomerular basement membrane.
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
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
Normal albuminuria
Urine:
<20 microgram/ min, <30 mg/ day
Low- grade albuminuria (“microalbuminuria”)
Urine:
20- 200 microg/ min
30- 300 mg/ day
Macroalbuminuria
Urine:
>200 microgram/ min
> 300 mg/ day
Low- grad albuminuria is a risk factor for what?
Diabetic nephropathy
Except Diabetic nephropathy, Low- grade albuminuria may also be risk factor for?
Cardiovascular disease
(True for non- diabetics as well).
Reduction of albuminuria descreases what?
The cardiovascular risk
Three factors influencing Macroangiopathy
- Diabetes mellitus
- Atherosclerosis
- Hypertension
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
What are the leading causes of death in patients with DM based on comorbidity and mortality data?
AMI and stroke
Percentage of patients with T2DM that will die of AMI or stroke?
80%
What is the mortality of ischaemic heart disease in patients with T1DM?
35%
What is the diabetic foot?
The classical manifestation of late complications.
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
Treatment of DM?
- SMBG (self- monitoring blood glucose)
- Insulin treatment
- Regular HbA1c measurement
- Education, follow up
- Lifestyle changes
What can be reduced by strict control of glucose level?
Both cardiovascular risk and late complications.
By simply replacing insulin will be enough to eliminate disease progression?
No.
IGT and IFG will in long term lead to?
MI and stroke
