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MD1 Metabolism > The Pathology of Diabetes > Flashcards

The Pathology of Diabetes Flashcards

1
Q

What does diabetes strictly refer to?

A

Abundant production of urine

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2
Q

What does diabetes mellitus mean?

A

Polyuria secondary to glycosuria because of hyperglycaemia

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3
Q

Is diabetes a single pathology?

A

No, it’s a group of conditions

Endpoint = chronic hyperglycaemia

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4
Q

Where is insulin produced?

A

Beta cells in pancreatic islets

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5
Q

How do insulin levels rise?

A

After meal > increased blood glucose

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6
Q

What does insulin do?

A

Promotes glucose uptake and utilisation in tissues

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7
Q

Which tissues have a high expression of the insulin receptor?

A

Adipose tissue
Muscle
Liver

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8
Q

What is the structure of the insulin receptor?

A

Tetramer

  • 2 alpha subunits - extracellular
  • 2 beta subunits - intracellular
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9
Q

What does insulin binding to the insulin receptor lead to?

A

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

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10
Q

What does acute hyperglycaemia in type 1 diabetes cause?

A

Produce ketones > acidosis
Hyperglycaemia
Worsening dehydration
Leads to diabetic ketoacidosis

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11
Q

What does acute hyperglycaemia in type 2 diabetes cause?

A

Severe hyperglycaemia
Increasing serum osmolarity
Lapse into hyperosmolar coma

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12
Q

What do the consequences of diabetes relate to?

A

Severity

Duration

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13
Q

Which organs do major changes in diabetes involve?

A

Blood vessels

  • Macrovascular = larger muscular and elastic arteries
  • Microvascular = capillaries and arterioles
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14
Q

What are the macrovascular effects of diabetes?

A

Atherosclerosis

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15
Q

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

A

Accelerated and more severe

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16
Q

Where do diabetic patients develop atherosclerosis?

A

Usual areas

  • Coronary arteries
  • Carotid arteries
  • Aorta
  • Iliac arteries
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17
Q

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

A

10 times higher

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18
Q

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

A

Macroscopically and histologically indistinguishable

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19
Q

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

A

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

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20
Q

What are the consequences of atherosclerosis?

A

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

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21
Q

In diabetics, what type of strokes are more common?

A

Infarcts

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22
Q

Which vessels are part of microvascular beds?

A

Arterioles - particularly susceptible to disease processes

Capillaries

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23
Q

What are the microvascular effects of diabetes?

A

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

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24
Q

What do microvascular complications of diabetes relate to?

A

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

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25
Q

What effect does glycosylation have on the proteins?

A

Don’t break down/break down slowly

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26
Q

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

A

Pink
Thick
Acellular

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27
Q

What are Schiff bases?

A

Initially reversible glycosylated proteins

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28
Q

What are advanced glycation end products?

A

Later stable glycosylated proteins

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29
Q

How can you decrease the risk of microvascular complications?

A

Tight glycaemic control

30
Q

What is the pathophysiology of diabetic nephropathy?

A

Glomerulus walls become thicker > more leaky > proteinuria

Much later > renal failure

31
Q

What is often the initial presentation of diabetic nephropathy?

A

Proteinuria

32
Q

What can you need if you have chronic renal failure?

A

Dialysis

Transplant

33
Q

What problems in the kidney does diabetic nephropathy cause?

A

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

34
Q

What is diabetic glomerulosclerosis?

A

Glycosylated proteins embedded in walls of glomeruli > leakiness

35
Q

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

A 
Scarred
Pale
Shrunken
Granular
Impaired function
36
Q

What do the lesions in diabetic nephropathy look like histologically?

A

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

37
Q

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

A

Thickened

38
Q

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

A

Diabetic nephropathy

39
Q

How common is diabetic retinopathy?

A

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

40
Q

What is the primary pathological process in diabetic retinopathy?

A

Ischaemia because of microvascular injury and reduced perfusion

41
Q

Why does vascular proliferation in diabetic retinopathy occur?

A

In response to ischaemia

42
Q

Are the changes of diabetic retinopathy visible with an ophthalmoscope?

A

Yes

43
Q

Why is there slower wound healing in diabetes?

A 
Impaired perfusion because of microvascular injury
Also partly because of
- Macrovascular disease
- Increased susceptibility to infection
- Possible neuropathy
44
Q

Why are foot ulcers difficult to treat in diabetes?

A

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

45
Q

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?

A

Amputation

46
Q

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

A

Creates wound on stump > slow to heal

47
Q

What is a critical part of management in diabetes?

A

Foot care

48
Q

Why is chronic hyperglycaemia damaging to tissue?

A

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
Q

What are advanced glycation end products?

A

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

50
Q

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

A

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

51
Q

What do the advanced glycation end products do?

A

Bind to receptor = RAGE

52
Q

Where is the RAGE receptor located?

A 
Inflammatory cells
- Macrophages
- T cells
Endothelial cells
Vascular smooth muscle
53
Q

What is the principle source of advanced glycation end products?

A

Diet

54
Q

When are advanced glycation end products associated with organ damage?

A

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

55
Q

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

A

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
Q

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

A

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
Q

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

A

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

58
Q

What activates protein kinace C in intracellular hyperglycaemia?

A

2nd messenger = diacyl glycerol (DAG)

Intracellular hyperglycaemia stimulates overproduction

59
Q

What does protein kinase C activation lead to?

A

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
Q

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

A

Yes

61
Q

How is excess intracellular glucose metabolised?

A

Through intermediates = polyols > to fructose

62
Q

What molecule does polyol metabolism use up?

A

Glutathione

63
Q

What is glutathione needed for?

A

Protects cells againt oxidative stress

64
Q

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

A

Reduction in available glutathione > cells vulnerable to oxidative stress

65
Q

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

A

Diabetic neuropathy

66
Q

What contributes to peripheral neuropathy in diabetes?

A

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

67
Q

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

A

Obesity
Dyslipidaemia
Hyperinsulinaemia and insulin resistance
Overt T2D

68
Q

What happens in NASH?

A

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

69
Q

Is NASH a consequence of diabetes?

A

Not clear if consequence

Right now considered close association

70
Q

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

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

MD1 Metabolism (18 decks)

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