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Pathology Term 3 > Week 1 - Diabetes Mellitus > Flashcards

Week 1 - Diabetes Mellitus Flashcards

1
Q

Describe the epidemiology of diabetes.

A
  • > 8% of world population, increasing, shortens life span by 15 years.
  • Most common lifestyle/non communicable disease.
  • Leading cause of blindness, kidney disease and leg amputation.
  • Developing countries - leaders in DM & obesity (marked increase in incidence).
  • Australia - 7th leading cause of death, 1 million diabetics - half unaware.
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2
Q

Outline the nature of diabetes.

A
  • Disorder of metabolism (carb, protein and fat) due to lack of insulin - deficiency (type 1)/resistance (type 2), many subtypes.
  • Characterised by polyuria, polydipsia and polyphagia with hyperglycemia.
  • Decreased glucose inside cells - cell starving, fatigue, damage and degeneration of cells.
  • Increased glucose out in blood - damage blood vessels (angiopathy) and tissues - CNS, kidneys, eyes.
  • Immunosuppressed state → infections
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3
Q

Describe the composition of the pancreas.

A 
2 main parts of the pancreas:
• Endocrine part - Islets of Langerhan
- Beta cells (80%) - insulin 
- Alpha cells (20%) - glucagon
- Delta cells (5%) - somatostatin
- PP cells (1%) - VIP
• Exocrine part - pancreatic acini (digestive enzymes)
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4
Q

What are the hormones involved in blood glucose control?

A 
Blood glucose is maintained between 3.5-5.5 by the following hormones:
• Insulin					Decreased glucose			
• Glucagon				Increased glucose
• Glucocortocoids			Increased glucose	
• Growth hormone			Increased glucose	
• Epinephrine				Increased glucose
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5
Q

Identify the functions of insulin.

A 
Insulin is anabolic steroid which functions to transport glucose in liver, muscle & adipose tissue:
• Liver
- Decreased gluconeogenesis
- Increased glycogen synthesis
- Increased lipogenesis
• Muscle
- Increased glucose uptake
- Increased glycogen synthesis
- Increased protein synthesis
• Adipose tissue
- Increased glucose uptake
- Increased lipogenesis
- Decreased lipolysis
• Acts on these tissues due to GLUT 4 receptors. Liver also has GLUT 2 receptors.
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6
Q

What are the symptoms of diabetes?

A

Fatigue, polyuria, polydipsia, polyphagia, infections.

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7
Q

What are the complications of diabetes?

A

Retinopathy, nephropathy, neuropathy, dermatopathy, arthropathy.

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8
Q

Outline the classification of primary diabetes.

A

Primary diabetes:
• Type 1 - IDDM/juvenile (5-10%).
• Type 2 - NIDDM/adult onset (90-95%).
• MODY - Maturity onset diabetes of youth (subtypes 1-6).
• LADA - Latent autoimmune diabetes in adults (adult type 1).
• GDM - gestational diabetes mellitus.
• Other - neonatal diabetes, insulin gene defects.

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9
Q

Outline the classification of secondary diabetes.

A

Secondary diabetes:
• Excess hyperglycaemic stimulus - Cushing’s, pheochromocytoma, acromegaly, steroid therapy.
• Beta cell destruction
- Pancreatitis/tumours/haemochromatosis (bronze diabetes).
- Infectious - congenital rubella, CMV, TB.
- Endocrinopathy, Down’s syndrome.

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10
Q

Describe the criteria for the diagnosis of diabetes.

A

1 or more of the following:

  1. Random blood glucose concentration of 11.1mmol/L or higher, with classical signs / symptoms
  2. Fasting blood glucose concentration of 7mmol/L or higher on more than one occasion.
  3. Abnormal oral glucose tolerance test (done for borderline readings between 5.5-6.9), in which the glucose concentration is >11.1mmol/L at 2 hours after a standard carbohydrate load (75mg of glucose).
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11
Q

What investigations aid in the classification of the type of diabetes?

A
  • C peptide levels - low in T1DM, normal or increased in T2DM.
  • Antibodies in T1DM e.g. GAD, ICA
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12
Q

Describe the aetiology of type 1 diabetes.

A

Autoimmune disease characterised by pancreatic β-cell destruction & absolute insulin deficiency.
• Genetic: HLA DR3,4
• Environmental: virus
• Autoimmune: GAD65, ICA512

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13
Q

Outline the pathogenesis of type 1 diabetes.

A

Autoimmune T cell destruction of pancreatic β cells:

  1. Genetic susceptibility to immune dysfunction + environmental triggers/regulators.
  2. Dysfunction in regulatory T cells.
  3. Insulitis → inflammatory cell infiltration of the pancreatic islets.
  4. Autoantibody mediated destruction of pancreatic β cells.
  5. Loss of insulin production.
  6. Hyperglycaemia / clinical symptoms (when 70-90% of β cells are destroyed).
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14
Q

Describe the morphology of type 1 diabetes.

A

Gross:
• Pancreatic lesions are inconstant & rarely of diagnostic value.
• ?Possible reduction in size (due reduction in number/size of islets).
Microscopy:
• Reduction in number and size of islets.
• Lymphocyte infiltrate in islets (insulitis).
• Eosinophilic infiltrates may also be found.
• Exocrine pancreas is normal.

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15
Q

Describe the aetiology of type 2 diabetes.

A

Combination of peripheral resistance to insulin & inadequate insulin secretion by β-cells.
• Genetic - monozygotic twins (>90%), family history (5-10 times), some gene loci (research).
• Environmental - obesity, lifestyle (lack of exercise), diet (high calorie).

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16
Q

Outline the pathogenesis of type 2 diabetes.

A

Exact mechanism of developing insulin resistance remains unclear.
• Central adipose tissue releases large quantities of FFA, adipokines and inflammatory mediators which induce insulin resistance.
• Compensatory β cell hyperplasia - increased insulin (normoglycaemia)
• Eventually β cells can’t compensate adequately & blood glucose rises - hyperglycaemia (early β cell failure - decreased insulin, impaired glucose tolerance).
• Late β cell failure (diabetes).
• Total β cell loss - IDDM (no insulin).

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17
Q

Describe the morphology of type 2 diabetes.

A

Gross:
• Pancreatic lesions are inconstant & rarely of diagnostic value.
• ?Possible reduction in size (due reduction in number/size of islets).
Microscopy:
• Early stage - islets appear normal or compensatory beta cell hyperplasia.
• Late stage - total beta cell loss - replaced by the protein amyloid.
• Exocrine pancreas is normal.

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18
Q

What is MODY?

A
  • Maturity Onset Diabetes of Youth (type 2 diabetes occurring in younger age).
  • 1-2% of clinical cases (most common of other types of diabetes).
  • Monogenic.
  • Subtypes 1-6.
  • MODY2 - glucokinase (GCK) mutation commonest.
19
Q

What is LADA?

A
  • Latent Autoimmune Diabetes in Adults AKA 1.5 DM/Type 3 DM (type 1 DM occurring in late age/adults).
  • Rapid onset, no obesity, difficult control, lack of response to oral therapy, early insulin dependency (all typical of T1DM).
20
Q

What is type A insulin resistance?

A
  • Monogenic.
  • Hyperglycaemia, hyperinsulinaemia and insulin resistance.
  • Insulin receptor mutations (aetiology)
  • Acanthosis nigricans is one of the clinical features - rough pigmented patches.
  • Females have PCOS.
21
Q

Outline type 1 diabetes.

A
  • Autoimmune disease - genetic + environment + autoimmune.
  • Children <25 years.
  • IDDM - acute onset. 5-10%.
  • Acute metabolic complications.
  • Difficult management.
  • . Autoantibodies
  • Family history (yes/no).
  • 50% in twins.
  • Microscopy - Insulitis - lymphocytic infiltrate within islets.
22
Q

Outline type 2 diabetes.

A
  • Genetic + lifestyle.
  • Adult >25 years.
  • . NIDDM - slow chronic.
  • Asymptomatic in early stage.
  • Chronic vascular complications.
  • No autoantibodies.
  • Family history.
  • 90% in twins.
  • Microscopy - Normal/amyloid deposition only in late stage (not AGE).
23
Q

Outline the pathogenesis of polyuria, polydipsia and polyphagia.

A
  • Polyuria - as increased glucose in urine → increased water in urine → increased urination.
  • Polydipsia - as increased glucose in blood → causes decreased intracellular water (due to osmotic movement) which triggers osmoreceptors in the thirst centre of the brain.
  • Polyphagia - as decreased cellular glucose → causes body to ‘need more glucose’ → increase appetite. Also decreased insulin causes catabolism of proteins & fats → amino acids used as building blocks for glucose (gluconeogenesis) → increased appetite.
24
Q

Identify the acute metabolic complications associated with diabetes.

A
  • Diabetic ketoacidosis
  • Hyperosmolar Hyperosmotic Syndrome (HHS/HONK)
  • Severe hypoglycaemia
  • Lactic acidosis
25
Q

Outline diabetic ketoacidosis.

A
  • Common in T1DM.
  • Severe hyperglycaemia, increased glucagon and epinephrine → osmotic diuresis and dehydration.
  • Lipolysis → FFA leading to ketonaemia and ketonuria → produces metabolic acidosis and dehydration. (Decreased insulin stimulates HSL → breakdown adipose tissue → increase fatty acids which become fatty-acetyl-CoA & oxidised to form ketone bodies as an energy source → increased ketones (production greater than excretion).
  • Fatigue, nausea, vomiting, Kussmaul breathing (deep and laboured).
26
Q

What is HONK?

A
  • Hyperosmolar non-ketotic syndrome.
  • Severe hyperglycemia, osmotic diuresis and lack of hydration.
  • Severe dehydration only, non ketotic, no acidosis - no nausea, vomiting or Kussmaul breathing.
  • Characterised by severe hyperglycaemia, without significant hyperketonaemia or acidosis.
27
Q

Outline hypoglycaemia

A

• Decreased glucose can occur in diabetes due to excess dose/overdose of drugs, excess insulin or lack of eating → causes sweating, palpitations, tachycardia, dizziness and confusion (severe hypoglycaemia causes CNS damage).

28
Q

Describe the pathogenesis of chronic (vascular) complications.

A

Insulin dependent tissues (striated muscle, fat, liver tissue):
• Low glucose inside cell - decreased metabolism. Starvation.

Insulin independent tissues (blood vessels, nerves, eyes, CNS):
• Excess glucose in cytoplasm and in blood vessels (hyperglycaemia).
- Glucose polymerisation → polyols (sorbitol) → osmotic damage.
- Activation of protein kinase C → inflammation, angiogenesis, fibrosis.
- Glycosylation → advanced glycosylation end products (AGE) damage BV wall → protein leakage → thickening (arteriolosclerosis) - ischaemia - microangiopathy.
- Increased atherosclerosis - macroangiopathy

29
Q

Outline the pathogenesis of microangiopathy.

A
  1. Hyperglycaemia.
  2. Glycosylation of basement proteins.
  3. AGE deposition - BV wall damage - leakage.
  4. More BM protein deposition.
  5. Thickening → hyaline arteriolosclerosis.
  6. Narrowing - ischaemia - BV & organ damage.
30
Q

Describe non-proliferative retinopathy.

A
  • Reversible.
  • Microaneurysms & dot blot haemorrhages.
  • Macular oedema.
  • Hard and soft exudates.
  • Cotton wool infarcts (microinfarcts due to ischemia which obscure underlying vessels).
  • Dot & blot retinal haemorrhages, deep-lying edema and lipid exudates impair macular function.
  • Late generalised decreased vision due to ischaemia and macula oedema – commonest cause of visual defect.

NB. Often due to exposure of lens epithelium to glucose – accumulation of intracellular sorbitol causes increased osmotic load within the lens, causing swelling, fibre breakdown & opacification.

31
Q

Describe proliferative retinopathy.

A
  • Irreversible.
  • Neovascularisation (new capillaries grow into the vitreous cavity).
  • Large haemorrhages (sudden vision loss).
  • Retinal detachment.
  • In advanced disease, neovascular membranes can occur resulting in traction & retinal detachment, leading to permanent blindness.
32
Q

Describe the pathogenesis of neuropathy.

A

Occurs due to polyol damage, ischaemia due to microangiopathy & demyelination – effects of demyelination is mainly seen on sensory nerves as motor nerves do not have myelin.

33
Q

Outline peripheral neuropathy.

A
  • Bilateral, symmetric.
  • Distal, pins and needles (glove and sock).
  • Progressive, irreversible.
  • Paraesthesia, pain, muscle atrophy - late.
  • Decreased sensation leads to injuries on the feet that go unfelt → neuropathic ulcers.
34
Q

Outline visceral neuropathy.

A

Involvement of cranial and visceral nerves:
• Cranial nerve → diplopia, Bells palsy.
• GIT → constipation, diarrhoea.
• CVS → orthostatic hypotension.

35
Q

Outline dermatopathy (skin disease).

A

Neuropathic Ulcer
• Peripheral sensory neuropathy, compromised with trauma, pressure and deformity.
• When combined with ischaemia usually seen in diabetics, is callous formation, oedema, thickening of the skin & results in ulcers.
• Features:
- Painless ulcer surrounded by callus (hyperkeratosis) at pressure points.
- Associated with good foot pulses (as cause is not vascular - blood flow not affected).
- May not be associated with gangrene.

36
Q

Explain the pathogenesis of nephropathy.

A

• Kidney damage is the most common cause of diabetic mortality.
1. AGE (advanced glycosylation end product) deposition occurs in loop of capillary (in mesangial cells) as round nodules of AGE protein (because glomerular capillaries are lined by impermeable foot processes).
2. Nodule compresses on capillaries causing lack of filtration in one glomeruli at a time (nodular glomerulosclerosis).
3. Glomerulus dies and is replaced by a fibrous scar (diffuse glomerulosclerosis).
4. Cause necrotising renal papillitis (papillary necrosis), nephritic syndrome, pyelonephritis & end-stage kidney
• Earliest manifestation is appearance of low amounts of albumin in urine - microalbuminuria (due to protein leakage).

37
Q

Describe the morphology of nephropathy

A
  • Nodular glomerulosclerosis (or Kimmelstein Wilson (KW) lesion).
  • Hyaline arteriolosclerosis.
  • Thickening of basement membrane (eg. proximal convoluted tubule).
38
Q

Outline macroangiopathy complications.

A

• Complications such as myocardial infarction, renal vascular insufficiency & cerebrovascular accidents are the most common causes of mortality in long-standing diabetes.
• Atherosclerosis is the main macroangiopathy in diabetes.
• It is a direct result of endothelial damage caused by AGE protein and leads to:
- Dyslipidemia.
- Low HDL.
- Non-enzymatic glycosylation.
- Increase platelet adhesiveness.
- Increase thromboxane A2.
- Decrease prostacyclin.
• This predisposes patient to MI, CVA, gangrene of leg (PVD) & renal insufficiency.

39
Q

Why are diabetics more prone to infections?

A

Multifactorial (not just increased glucose):
1. Impaired inflammation response - BV sclerosis.
2. WBC, endothelium, damage by glycosylation.
3. Glycosylation of chemical mediators of inflammation.
4. Decreased metabolism - cell starving.
5. Tissue ischaemia and infarctions.
6. Increased glucose (alone is not the cause*).
• Fungal infections very common in diabetes because of immunosuppression - particularly Candida infections, aspergillosis etc.

40
Q

What are the effects of gestational diabetes on the newborn?

A

Macrosomia + polycythemia.

41
Q

Describe cataract formation in diabetes.

A

Cataract formation due to polyol induced damage in lens epithelium. (Polyol formation in lens).

42
Q

What is diabetic xanthoma?

A
  • Seen in severe diabetics with markedly increased lipid levels (very high blood glucose and hyperlipidaemia).
  • Reddish yellow, pruritic, painful vesicles.
  • Subcutaneous fat necrosis, foamy macrophages and free lipids (produce skin lesions which are deposits of fat necrosis with foamy macrophages).
  • When they occur suddenly and multiple → eruptive xanthoma - severe.
43
Q

What is the incretin effect?

A

• Food in GIT → stimulates incretins - GIP & GLP-1.
• These hormones stimulate the pancreas to cause insulin secretion and suppression of glucagon (incretin effect).
• These incretins are rapidly destroyed normally in the body by dipeptidyl peptidase (DPP4).
• Abnormality of incretin response → T2DM.
• 2 new drugs - both cause increased incretin effects:
- Exenatide (GLP-1 receptor agonist).
- Gliptins (DPP4 inhibitor).

44
Q

What are the other effects of incretins in the body?

A
  • Stimulates hypothalamus to stimulate the satiety centre - person feels they are full.
  • Produces gluconeogenesis.
  • Causes adipose tissue lipogenesis.

Pathology Term 3 (6 decks)

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