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Flashcards in The Pathology of Diabetes Deck (70):
1

What does diabetes strictly refer to?

Abundant production of urine

2

What does diabetes mellitus mean?

Polyuria secondary to glycosuria because of hyperglycaemia

3

Is diabetes a single pathology?

No, it's a group of conditions
Endpoint = chronic hyperglycaemia

4

Where is insulin produced?

Beta cells in pancreatic islets

5

How do insulin levels rise?

After meal > increased blood glucose

6

What does insulin do?

Promotes glucose uptake and utilisation in tissues

7

Which tissues have a high expression of the insulin receptor?

Adipose tissue
Muscle
Liver

8

What is the structure of the insulin receptor?

Tetramer
- 2 alpha subunits - extracellular
- 2 beta subunits - intracellular

9

What does insulin binding to the insulin receptor lead to?

Tyrosine phosphorylation of substrate proteins
Translocation of glucose transport proteins to surface
Alteration to lipid and glucose metabolism

10

What does acute hyperglycaemia in type 1 diabetes cause?

Produce ketones > acidosis
Hyperglycaemia
Worsening dehydration
Leads to diabetic ketoacidosis

11

What does acute hyperglycaemia in type 2 diabetes cause?

Severe hyperglycaemia
Increasing serum osmolarity
Lapse into hyperosmolar coma

12

What do the consequences of diabetes relate to?

Severity
Duration

13

Which organs do major changes in diabetes involve?

Blood vessels
- Macrovascular = larger muscular and elastic arteries
- Microvascular = capillaries and arterioles

14

What are the macrovascular effects of diabetes?

Atherosclerosis

15

What is the rate of progression and severity of atherosclerosis in diabetes?

Accelerated and more severe

16

Where do diabetic patients develop atherosclerosis?

Usual areas
- Coronary arteries
- Carotid arteries
- Aorta
- Iliac arteries

17

What is the risk for cardiovascular events in type 1 diabetics compared to age-matched non-diabetics?

10 times higher

18

How can you tell atherosclerosis apart in diabetics and non-diabetics?

Macroscopically and histologically indistinguishable

19

What are some of the factors that contribute to atherosclerosis in diabetics?

Increased hepatic production of atherogenic lipoproteins
Suppression of lipid uptake in peripheral tissues
Abnormal endothelial function with pro-coagulant results
Associated abnormalities frequently seen in diabetes including
- Hyperlipidaemia
- Hypertension

20

What are the consequences of atherosclerosis?

Myocardial infarction
Thrombotic stroke
Infarcts in peripheral tissues; eg: toes

21

In diabetics, what type of strokes are more common?

Infarcts

22

Which vessels are part of microvascular beds?

Arterioles - particularly susceptible to disease processes
Capillaries

23

What are the microvascular effects of diabetes?

Kidney > diabetic nephropathy
Retina > diabetic retinopathy
Delayed wound healing
Foot ulcers

24

What do microvascular complications of diabetes relate to?

Long term effects of hyperglycaemia on cells and extracellular matrix
Especially glycosylation of proteins

25

What effect does glycosylation have on the proteins?

Don't break down/break down slowly

26

What do glycosylated proteins look like in a H&E stain?

Pink
Thick
Acellular

27

What are Schiff bases?

Initially reversible glycosylated proteins

28

What are advanced glycation end products?

Later stable glycosylated proteins

29

How can you decrease the risk of microvascular complications?

Tight glycaemic control

30

What is the pathophysiology of diabetic nephropathy?

Glomerulus walls become thicker > more leaky > proteinuria
Much later > renal failure

31

What is often the initial presentation of diabetic nephropathy?

Proteinuria

32

What can you need if you have chronic renal failure?

Dialysis
Transplant

33

What problems in the kidney does diabetic nephropathy cause?

Diabetic glomerulosclerosis/arteriolosclerosis
Infection - also because of affected neutrophil function
Papillary necrosis
Accelerated atherosclerosis in larger arteries

34

What is diabetic glomerulosclerosis?

Glycosylated proteins embedded in walls of glomeruli > leakiness

35

What do kidneys look like macroscopically in late stage diabetic nephropathy?

Scarred
Pale
Shrunken
Granular
Impaired function

36

What do the lesions in diabetic nephropathy look like histologically?

Kimmelstiel-Wilson nodules = spherical nodules in mesangium > become balls of collagen
Hyaline arteriolosclerosis = arteriolar wall thickening by acellular proteinaceous material

37

What does the glomerular basement membrane in diabetic nephropathy look like under the electron microscope?

Thickened

38

What is the most common cause of end stage kidney disease?

Diabetic nephropathy

39

How common is diabetic retinopathy?

Occurs to some degree in up to 80% of diabetics after 20 years

40

What is the primary pathological process in diabetic retinopathy?

Ischaemia because of microvascular injury and reduced perfusion

41

Why does vascular proliferation in diabetic retinopathy occur?

In response to ischaemia

42

Are the changes of diabetic retinopathy visible with an ophthalmoscope?

Yes

43

Why is there slower wound healing in diabetes?

Impaired perfusion because of microvascular injury
Also partly because of
- Macrovascular disease
- Increased susceptibility to infection
- Possible neuropathy

44

Why are foot ulcers difficult to treat in diabetes?

Poor wound healing
Difficulty eradication infection
Neuropathy
Leads to repeated minor trauma

45

What is often the only option in treating foot ulcers in diabetes, so that the person is able to return to a mobile, active life?

Amputation

46

What is the problem with amputation as a treatment for foot ulcers in diabetes?

Creates wound on stump > slow to heal

47

What is a critical part of management in diabetes?

Foot care

48

Why is chronic hyperglycaemia damaging to tissue?

3 possible metabolic pathways, unclear which is more important
- Advanced glycation end products
- Activation of protein kinase C
- Intracellular hyperglycaemia and abnormal polyol pathways

49

What are advanced glycation end products?

Reactions between molecules derived from glucose and amino groups of proteins inside and outside cells

50

Are advanced glycation end products possible in people without diabetes? If so, how are they different in people with diabetes?

Yes, form normally, but rate of formation shoots up in hyperglycaemia

51

What do the advanced glycation end products do?

Bind to receptor = RAGE

52

Where is the RAGE receptor located?

Inflammatory cells
- Macrophages
- T cells
Endothelial cells
Vascular smooth muscle

53

What is the principle source of advanced glycation end products?

Diet

54

When are advanced glycation end products associated with organ damage?

Levels become high and remain chronically increased like in diabetes and ageing

55

What do high levels of advanced glycated end products lead to?

Release of pro-inflammatory cytokines and growth factors from macrophages
Generation of ROS in endothelial cells
Increased pro-coagulant activity in endothelial cells
Proliferation and matrix production by vascular smooth muscle cells

56

What are the effects of advanced glycated end products not mediated by RAGE?

Cross link extracellular matrix proteins
- Cross link type I collagen in vessel walls > alters dynamics > vessel injury
- Cross linking of type IV collagen in basement membranes > alters attachment of endothelium and permeability > thickens basement membrane

57

Why are proteins cross linked because of advanced glycated end products a problem?

Resistant to degradation
Advanced glycated end product-bound matrix proteins trap other proteins including LDL > possible explanation for accelerated atherosclerosis

58

What activates protein kinace C in intracellular hyperglycaemia?

2nd messenger = diacyl glycerol (DAG)
Intracellular hyperglycaemia stimulates overproduction

59

What does protein kinase C activation lead to?

Pro-angiogenic growth factors; eg: VEGF
Elevated endothelin-1 and reduced NO > tendency to small vessel constriction
Pro-fibrogenic growth factors; eg: TGF-beta > increased production of basement membrane and matrix
Pro-inflammatory cytokines from endothelium

60

Do tissues without insulin receptors have higher intracellular glucose concentrations with persisting hyperglycaemia?

Yes

61

How is excess intracellular glucose metabolised?

Through intermediates = polyols > to fructose

62

What molecule does polyol metabolism use up?

Glutathione

63

What is glutathione needed for?

Protects cells againt oxidative stress

64

What happens to glutathione levels, and what are the consequences, in sustained elevated intracellular glucose?

Reduction in available glutathione > cells vulnerable to oxidative stress

65

What pathology could be more likely to happen because of increased polyol metabolism in diabetes?

Diabetic neuropathy

66

What contributes to peripheral neuropathy in diabetes?

Advanced glycated end product-related damage > loss of axons
Possibly polyol related damage
Microvascular injury > neuronal ischaemia

67

What is non-alcoholic steatohepatitis (NASH) associated with?

Obesity
Dyslipidaemia
Hyperinsulinaemia and insulin resistance
Overt T2D

68

What happens in NASH?

Fat accumulates in liver cells
Infiltrate of neutrophils and lymphocytes
Liver cell damage
Eventually fibrosis

69

Is NASH a consequence of diabetes?

Not clear if consequence
Right now considered close association

70

How can you divide the complications of diabetes into three categories?

Macrovascular/atherosclerosis
Microvascular
Cellular (non-vascular)
- Neutrophil dysfunction
- Peripheral nerves
- Hepatocytes
- CNS cell populations; eg: dementia
- Others