Pathology of Diabetes Mellitus (P.Brown) Flashcards
what is the normal appearance of the pancreas
lobules of glandular tissue surrounded by fat - septae between lobules
what are the islets of langerhans
make up the endocrine pancreas - 2/3 of islets cells are B cells that secrete insulin
how does insulin act on fat
insulin binds to receptors and drives glucose into adipocytes (fat cells)
what is the basic glucose metabolism pathway
increased glucose in plasma = increased insulin = increased glucose uptake by cells = decreased glucose in plasma
what is the aetiology of type I DM
- aetiology not entirely known
1. genes + 2. environment = destruction of B cells
what are the genes involved in type I
genes that code for molecules that help T cells recognise self from non-self (human leukocyte antigen (HLA) molecules)
what happens when there is a faulty gene that then leads to type I
T cells cannot distinguish own cells from other cells - leads to autoimmune attack on pancreatic B cells - destruction of B cells = decreased insulin
what kind of environmental triggers are involved in type I
- ? chemicals
2. ? viral infection - ? molecules on viral surface mimic molecules on outside of B - immune attack
what does destruction of B cells cause
decrease in insulin - increase in glucose in plasma
what is the aetiology of type 2 DM
- aetiology not entirely known but COMBINATION of:
- reduced tissue sensitivity to insulin (insulin resistance)
- inability to secrete very high levels of insulin
ie - failure of B cells to met an increased demand for insulin in the body
what type of increased body mass is important in type 2
expanded upper body visceral fat mass (i.e. pot belly) due to increased food intake + lack of exercise (genes not important)
- not just high BMI - specifically weight put on around the abdomen and fat in the momentum inside i.e. doesn’t include the weight many women put on around butt and thighs
what does a “pot belly” result in
increased free fatty acids in blood due to “overweight” adipocytes become “stressed” and release fatty acids
(patient not yet diabetic though)
what does increased FFA’s in the blood lead to
decreased insulin receptor sensitivity
what effect does decreased insulin receptor sensitivity have on the pancreas
Pancreas has to secrete more insulin:
some glucose gets into cells but some does not - needs MORE insulin to get the same amount of glucose into cells
= hyperinsulinaemia (NOT diabetic yet)
summarise what happens in hyperinsulinaemia (peripheral insulin resistance) to get blood glucose levels back to normal
decreased insulin receptor sensitivity - decreased removal of glucose from blood - increased glucose levels in blood - increase in section of insulin from pancreas - increased insulin in blood - blood glucose levels return to normal
many genes control insulin secretion in the pancreas - what can they determine with regards to this
whether an individual can secrete very large amounts of insulin or not
how would a few abnormal genes affect insulin production
can still produce large amounts of insulin
how would many abnormal genes affect insulin production
cannot produce large amounts of insulin - implicated genes appear to be or poor B cell “high end” insulin secretion
how do many abnormal genes lead to type 2
cannot produce large amounts of insulin - insulin levels not high enough to counteract insulin resistance caused by central adiposity
summarise how blood glucose is maintained in people with normal weight
insulin increases - blood glucose deceases - blood glucose normal
summarise how type 1 occurs
b cells destroyed - insulin decreases - blood glucose increases - type 1
summarise how blood glucose is maintained in people with central adiposity BUT many genes for high end insulin secretion
central adiposity - peripheral insulin resistance - glucose increases - huge increase in insulin - decreases glucose - normal blood glucose
(NOT DIABETIC)
summarise how type 2 diabetes occurs
central adiposity + numerous defective genes for high end insulin secretion - glucose increases - insulin levels CANNOT be raised - blood glucose increases - type 2
how could a slim person get type 2
many abnormal genes for producing insulin - small weight gain - cannot even modestly raise insulin - type 2
what are long term complications of DM
- life expectancy decreased by 5-10 yrs
- myocardial infarction commonest cause of death
- main complications are damage to vessels (large and small)
All arise from poor glycemic control
what are large vessel complications of DM
macrovascular - ACCELERATION of atherosclerosis
*does not cause it
how does DM accelerate atherosclerosis
causes hyperlipidaemia which leads to atherosclerosis
how does hyperlipidaemia come about in DM
increased glucose attaches to low density lipoprotein - stops LDLP from binding to receptor on liver cells - not removed by liver cells - stay in blood = HYPERLIPIDAEMIA
what are small vessel complications of DM
microvascular - arteriolar disease (hyaline change), capillary damage
what forms the arteriole lining
several endothelial cells that make a basal lamina to “sit on” - around basal lamina smooth muscle cells
what lies between the basal lamina and endothelial cells
potential space where molecules flux in and out (at same rate)
what happens to the flux of molecules in/out the basal lamina in DM
flux in is bigger than flux out
how does this decreased flux out of the potential space lead to arteriolar disease
build up of trapped molecules under endothelial cells (e.g. albumin and collagen) - basal lamina becomes thickened - lumen becomes narrow - leads to poor blood flow = ISCHAEMIA throughout body
what areas are particularly damaged by arteriolar disease
kidneys, peripheral tissues (feet), eyes, arterioles supplying nerves
what happens to capillaries on small vessel disease
increased connective tissue around capillaries - e.g. glomerulus in kidney
what is the mechanism that leads to build up of trapped molecules in the basal lamina
glycosylation - glucose added to proteins
- non-enzymatic
- reversible at first
when does glycosylation become irreversible
if covalent bonds form - advanced glycosylation end-products (AGE’s)
describe how glycosylation leads to build up of molecules in the basal lamina
collagen in the basal lamina is glycosylated - albumin (+ other proteins) bind to glycosylated collagen - glycosylated proteins also form crosslinks with each other - cannot be easily removed
what happens to the cross linked glycosylated proteins in arteriole walls if the body returns to normal blood glucose levels
proteins persist in walls even when blood glucose back to normal due to advanced stage of glycosylation - AGE
