Pathology of Diabetes Mellitus (DM)

Question 1

what is the appearance of a normal pancreas?

Answer 1

lobules of glandular tissue surrounded by fat

lobules separated by septums

Question 2

what makes up the endocrine pancreas?

Answer 2

islets of langerhans

Question 3

what are 2/3 of islet cells?

Answer 3

B cells

Question 4

what do B cells secrete?

Answer 4

insulin

Question 5

what stimulates insulin?

Answer 5

Intake of food – converted to glucose

Question 6

where is insulin secreted into?

Answer 6

blood in capillaries

Question 7

what tissues does insulin act on?

Answer 7

various tissues – eg fat

Question 8

what does insulin bind to?

Answer 8

Insulin binds its receptor and drives glucose into adipocytes (= fat cells)

Question 9

what does the glucose metabolism pathway require?

Answer 9

Question 10

what is the aetiology of type one diabetes mellitus?

Answer 10

not known

Genes found so far =
Molecules that help T cells recognise self from non-self = Human Leukocyte Antigen (HLA) molecules

Question 11

what happens in type 1 diabetes mellitus?

Answer 11

Cannot distinguish own cells from other cells 🡪 autoimmune attack on pancreatic B cells

Autoimmune attack on islet cells – lymphocyte infiltration of islets (insulitis) – destruction of B cells

this decreases insulin

Question 12

what is the aetiology of type 2 diabetes mellitus?

Answer 12

Not entirely known

Combination of:
1) reduced tissue sensitivity to insulin (insulin resistance) and
2) inability to secrete very high levels of insulin

a failure of the B cells to meet an increased demand for insulin in the body

Question 13

what is the characteristic appearacne of someone with type 2 diabetes?

Answer 13

Expanded upper body visceral fat mass (pot belly)

Expanded upper body fat mass is due to increased intake of food + lack of exercise (genes relatively unimportant)

Question 14

what does expanded upper body visceral fat mass result in?

Answer 14

increased free fatty acids in blood

because ‘overweight’ adipocytes are probably ‘stressed’ and release fatty acids

Expanded upper body visceral fat mass leads to increased free fatty acids which leads to decreased insulin receptor sensitivity

Question 15

why is insulin receptor sensitivity decreased by expanded upper body fat mass?

Answer 15

not clear why the fatty acids interfere with the insulin receptor pathway

Question 16

what is the sequence of events for a type 2 prediabetic following reduced sensitivity to insulin?

Answer 16

Some glucose (Glc) gets into cells but some does not

need more insulin to get same amount of glucose into cells, pancreas in higher demand

So pancreas needs to secrete more insulin to move glucose into cells in person with central adiposity

Decreased removal of glucose from blood
leads to raised glucose, and insulin levels then have to markedly increase to make glucose go back to normal levels

Question 17

what leads to peripheral insulin resistance?

Answer 17

upper body visceral fat mass leads to peripheral insulin resistance

No diabetes will occur if can insulin substantially

Question 18

If peripheral insulin resistance
is present how do we keep glucose levels normal?

Answer 18

Need pancreas that produces more and more insulin

Question 19

Which genes control insulin secretion in pancreas?

Answer 19

Many different genes
Some of these genes control whether you can secrete very large amounts of insulin or not

Question 20

Which genes control insulin secretion in pancreas?

Answer 20

If gene is a variant it may promote insulin production at low levels but not high levels

Question 21

Type II DM = What type of genes are involved?

Answer 21

Implicated genes are for poor B cell ‘high end’ insulin secretion

So if you have only a few genes abnormal you will be able to secrete lots of insulin

if a patient has many gene variants for lower insulin secretion and cannot produce large amounts of insulin

Question 22

Answer 22

Question 23

define type two diabetes in terms of insulin secretion?

Answer 23

So in type II diabetes insulin secretion does not increase enough to counteract insulin resistance caused by central adiposity

Question 24

what may be an abnormality in a patient getting type 2 diabetes?

Answer 24

Slim person who puts on a small amount of weight may get type II diabetes if they have very high dosage of genes resulting in inability to even modestly raise insulin

Question 25

describe the genes involved in type 2 diabetes?

Answer 25

Multiple genes involved in causing inadequate ‘high level’ insulin secretion by B cells
Not HLA genes
Not adiposity genes

Question 26

define type 2 diabetes?

Answer 26

A multiple gene defect of pancreatic B cell insulin production which is unmasked by central adiposit

Question 27

what are long term complications for diabetic patients?

Answer 27

Annual mortality is 5.4% - double the rate of non-diabetics

Life expectancy is decreased by 5-10 years

Myocardial infarction is the commonest cause of death

Question 28

when do long term complications for diabetic patients arise?

Answer 28

Occur regardless of the cause of the DM

Result from prolonged poor glycaemic control

Question 29

what is the main complication of diabetes?

Answer 29

damage to small and large vessels

large - arteries
small - arterioles, capillaries

Question 30

what does diabetes mellitus accelarate?

Answer 30

atherosclerosis

Coronary heart disease 2-20x
Myocardial infarction 2-5x
Atherothrombotic stroke 2-3x

Question 31

how is atherosclerosis accelarated in diabetes mellitus?

Answer 31

glucose attach to LDL ussually

Glucose molecules stop low density lipoprotein from binding its receptor (on liver cells) tightly.

Low density lipoprotein is not removed by liver cells 🡪 lipoprotein and lipid stay in blood 🡪 Hyperlipidaemia

hyperlipidemia leads to atherosclerosis

Question 32

what effect does DM have on molecules diffusion?

Answer 32

Diabetes Mellitus – molecules flux into subendothelial space but find it hard to flux back to blood

Build up of ‘trapped’ molecules under endothelial cell

Basal lamina also becomes thickened

Question 33

what is arteriolar disease also known as?

Answer 33

hyaline change

Question 34

what effect does hyaline change have?

Answer 34

Process occurs throughout body
Narrow arteriole 🡪 poor blood flow 🡪 ischaemia

Very damaging in kidney, peripheral tissues (foot), eyes and in arterioles supplying nerves

Amputation 40x
End stage renal disease 25x
Blindness 20x

Question 35

small vessel disease?

Answer 35

Increased connective tissue around capillaries – eg. Glomerulus in kidney

Question 36

how does small vessel disease occur

Answer 36

1 mechanism = Glucoses added to proteins = glycosylation
Non-enzymatic
Reversible at 1st
Irreversible if covalent bonds = Advanced Glycosylation End-products = AGE’s

Question 37

what is a mechanism of edothelial thickening through glycoslation?

Answer 37

Advanced glycosylation products and small vessels - eg 1: Collagen is glycosylated
Collagen is in normal basal lamina
Albumin can sometimes get into subendothelial space
Normal collagen does not bind albumin
🡪 albumin fluxes out of space - no accumulation of albumin in subendothelial space of arterioles
Glycosylated collagen does bind albumin
🡪 Accumulation of albumin in subendothelial space of arterioles
Albumin is trapped in subendothelial space

Accumulation of albumin in subendothelial space of arterioles

Advanced glycosylation products and small vessels - eg 2: Proteins are cross-linked

Many normal basal lamina proteins do not crosslink and can be removed easily

But glycosylated proteins bind their neighbouring proteins
Rigid, cross-linked protein cannot easily be removed

Persistence of proteins in arteriole walls

Persistence even if return to normoglycaemia

Question 38

what is glycoslation?

Answer 38

Accumulation of trapped plasma proteins +
Accumulation of cross-linked basal lamina proteins

Question 39

is Large and small vessel disease in DM reversible?

Answer 39

no
Typically irreversible when established
Occurs in setting of prolonged, poor diabetic control