Pathology of Diabetes Mellitus (DM) Flashcards
what is the appearance of a normal pancreas?
lobules of glandular tissue surrounded by fat
lobules separated by septums
what makes up the endocrine pancreas?
islets of langerhans
what are 2/3 of islet cells?
B cells
what do B cells secrete?
insulin
what stimulates insulin?
Intake of food – converted to glucose
where is insulin secreted into?
blood in capillaries
what tissues does insulin act on?
various tissues – eg fat
what does insulin bind to?
Insulin binds its receptor and drives glucose into adipocytes (= fat cells)
what does the glucose metabolism pathway require?
what is the aetiology of type one diabetes mellitus?
not known
Genes found so far =
Molecules that help T cells recognise self from non-self = Human Leukocyte Antigen (HLA) molecules
what happens in type 1 diabetes mellitus?
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
what is the aetiology of type 2 diabetes mellitus?
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
what is the characteristic appearacne of someone with type 2 diabetes?
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)
what does expanded upper body visceral fat mass result in?
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
why is insulin receptor sensitivity decreased by expanded upper body fat mass?
not clear why the fatty acids interfere with the insulin receptor pathway
what is the sequence of events for a type 2 prediabetic following reduced sensitivity to insulin?
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
what leads to peripheral insulin resistance?
upper body visceral fat mass leads to peripheral insulin resistance
No diabetes will occur if can insulin substantially
If peripheral insulin resistance
is present how do we keep glucose levels normal?
Need pancreas that produces more and more insulin
Which genes control insulin secretion in pancreas?
Many different genes
Some of these genes control whether you can secrete very large amounts of insulin or not
Which genes control insulin secretion in pancreas?
If gene is a variant it may promote insulin production at low levels but not high levels
Type II DM = What type of genes are involved?
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
define type two diabetes in terms of insulin secretion?
So in type II diabetes insulin secretion does not increase enough to counteract insulin resistance caused by central adiposity
what may be an abnormality in a patient getting type 2 diabetes?
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
describe the genes involved in type 2 diabetes?
Multiple genes involved in causing inadequate ‘high level’ insulin secretion by B cells
Not HLA genes
Not adiposity genes
define type 2 diabetes?
A multiple gene defect of pancreatic B cell insulin production which is unmasked by central adiposit
what are long term complications for diabetic patients?
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
when do long term complications for diabetic patients arise?
Occur regardless of the cause of the DM
Result from prolonged poor glycaemic control
what is the main complication of diabetes?
damage to small and large vessels
large - arteries
small - arterioles, capillaries
what does diabetes mellitus accelarate?
atherosclerosis
Coronary heart disease 2-20x
Myocardial infarction 2-5x
Atherothrombotic stroke 2-3x
how is atherosclerosis accelarated in diabetes mellitus?
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
what effect does DM have on molecules diffusion?
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
what is arteriolar disease also known as?
hyaline change
what effect does hyaline change have?
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
small vessel disease?
Increased connective tissue around capillaries – eg. Glomerulus in kidney
how does small vessel disease occur
1 mechanism = Glucoses added to proteins = glycosylation
Non-enzymatic
Reversible at 1st
Irreversible if covalent bonds = Advanced Glycosylation End-products = AGE’s
what is a mechanism of edothelial thickening through glycoslation?
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
what is glycoslation?
Accumulation of trapped plasma proteins +
Accumulation of cross-linked basal lamina proteins
is Large and small vessel disease in DM reversible?
no
Typically irreversible when established
Occurs in setting of prolonged, poor diabetic control
