The Pathology of Diabetes

Question 1

What does diabetes strictly refer to?

Answer 1

Abundant production of urine

Question 2

What does diabetes mellitus mean?

Answer 2

Polyuria secondary to glycosuria because of hyperglycaemia

Question 3

Is diabetes a single pathology?

Answer 3

No, it’s a group of conditions

Endpoint = chronic hyperglycaemia

Question 4

Where is insulin produced?

Answer 4

Beta cells in pancreatic islets

Question 5

How do insulin levels rise?

Answer 5

After meal > increased blood glucose

Question 6

What does insulin do?

Answer 6

Promotes glucose uptake and utilisation in tissues

Question 7

Which tissues have a high expression of the insulin receptor?

Answer 7

Adipose tissue
Muscle
Liver

Question 8

What is the structure of the insulin receptor?

Answer 8

Tetramer

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

Question 9

What does insulin binding to the insulin receptor lead to?

Answer 9

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

Question 10

What does acute hyperglycaemia in type 1 diabetes cause?

Answer 10

Produce ketones > acidosis
Hyperglycaemia
Worsening dehydration
Leads to diabetic ketoacidosis

Question 11

What does acute hyperglycaemia in type 2 diabetes cause?

Answer 11

Severe hyperglycaemia
Increasing serum osmolarity
Lapse into hyperosmolar coma

Question 12

What do the consequences of diabetes relate to?

Answer 12

Severity

Duration

Question 13

Which organs do major changes in diabetes involve?

Answer 13

Blood vessels

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

Question 14

What are the macrovascular effects of diabetes?

Answer 14

Atherosclerosis

Question 15

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

Answer 15

Accelerated and more severe

Question 16

Where do diabetic patients develop atherosclerosis?

Answer 16

Usual areas

• Coronary arteries
• Carotid arteries
• Aorta
• Iliac arteries

Question 17

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

Answer 17

10 times higher

Question 18

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

Answer 18

Macroscopically and histologically indistinguishable

Question 19

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

Answer 19

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

Question 20

What are the consequences of atherosclerosis?

Answer 20

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

Question 21

In diabetics, what type of strokes are more common?

Answer 21

Infarcts

Question 22

Which vessels are part of microvascular beds?

Answer 22

Arterioles - particularly susceptible to disease processes

Capillaries

Question 23

What are the microvascular effects of diabetes?

Answer 23

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

Question 24

What do microvascular complications of diabetes relate to?

Answer 24

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

Question 25

What effect does glycosylation have on the proteins?

Answer 25

Don't break down/break down slowly

Question 26

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

Answer 26

Pink Thick Acellular

Question 27

What are Schiff bases?

Answer 27

Initially reversible glycosylated proteins

Question 28

What are advanced glycation end products?

Answer 28

Later stable glycosylated proteins

Question 29

How can you decrease the risk of microvascular complications?

Answer 29

Tight glycaemic control

Question 30

What is the pathophysiology of diabetic nephropathy?

Answer 30

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

Question 31

What is often the initial presentation of diabetic nephropathy?

Answer 31

Proteinuria

Question 32

What can you need if you have chronic renal failure?

Answer 32

Dialysis | Transplant

Question 33

What problems in the kidney does diabetic nephropathy cause?

Answer 33

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

Question 34

What is diabetic glomerulosclerosis?

Answer 34

Glycosylated proteins embedded in walls of glomeruli > leakiness

Question 35

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

Answer 35

``` Scarred Pale Shrunken Granular Impaired function ```

Question 36

What do the lesions in diabetic nephropathy look like histologically?

Answer 36

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

Question 37

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

Answer 37

Thickened

Question 38

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

Answer 38

Diabetic nephropathy

Question 39

How common is diabetic retinopathy?

Answer 39

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

Question 40

What is the primary pathological process in diabetic retinopathy?

Answer 40

Ischaemia because of microvascular injury and reduced perfusion

Question 41

Why does vascular proliferation in diabetic retinopathy occur?

Answer 41

In response to ischaemia

Question 42

Are the changes of diabetic retinopathy visible with an ophthalmoscope?

Answer 42

Yes

Question 43

Why is there slower wound healing in diabetes?

Answer 43

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

Question 44

Why are foot ulcers difficult to treat in diabetes?

Answer 44

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

Question 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?

Answer 45

Amputation

Question 46

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

Answer 46

Creates wound on stump > slow to heal

Question 47

What is a critical part of management in diabetes?

Answer 47

Foot care

Question 48

Why is chronic hyperglycaemia damaging to tissue?

Answer 48

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

Question 49

What are advanced glycation end products?

Answer 49

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

Question 50

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

Answer 50

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

Question 51

What do the advanced glycation end products do?

Answer 51

Bind to receptor = RAGE

Question 52

Where is the RAGE receptor located?

Answer 52

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

Question 53

What is the principle source of advanced glycation end products?

Answer 53

Diet

Question 54

When are advanced glycation end products associated with organ damage?

Answer 54

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

Question 55

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

Answer 55

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

Question 56

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

Answer 56

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

Question 57

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

Answer 57

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

Question 58

What activates protein kinace C in intracellular hyperglycaemia?

Answer 58

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

Question 59

What does protein kinase C activation lead to?

Answer 59

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

Question 60

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

Answer 60

Yes

Question 61

How is excess intracellular glucose metabolised?

Answer 61

Through intermediates = polyols > to fructose

Question 62

What molecule does polyol metabolism use up?

Answer 62

Glutathione

Question 63

What is glutathione needed for?

Answer 63

Protects cells againt oxidative stress

Question 64

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

Answer 64

Reduction in available glutathione > cells vulnerable to oxidative stress

Question 65

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

Answer 65

Diabetic neuropathy

Question 66

What contributes to peripheral neuropathy in diabetes?

Answer 66

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

Question 67

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

Answer 67

Obesity Dyslipidaemia Hyperinsulinaemia and insulin resistance Overt T2D

Question 68

What happens in NASH?

Answer 68

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

Question 69

Is NASH a consequence of diabetes?

Answer 69

Not clear if consequence | Right now considered close association

Question 70

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

Answer 70

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