Pathology of Diabetes Mellitus Flashcards
What is the pancreas composed of?
Lobules of glandular tissue surrounded by fat
What part of the pancreas is the endocrine pancreas?
Islets of Langerhans
How many of the Islet of Langerhan cells are B cells?
2/3
What does insulin do?
Acts on many tissues, such as fat, where is binds to its receptor and drives glucose into the cell
Explain the pathway of increases glucose in plasma leading to glucose decreasing?
What genetic relationship to the aetiology of type 1 diabetes has been found?
- HLA (human leukocyte antigen) molecules help T cells recognise self from non-self
- in type 1 diabetes cannot distinguish own cells from other cells = autoimmune attack on B cells
What does the autoimmune attack on B cells in type 1 diabetes cause?
Lymphocyte infiltration of islet (insulitis) leading to destruction of B cells causing decreases insulin production
What environmental triggers are possible linked to type 1 diabetes?
? Chemicals
? Bacteria in gut altered in infancy
? Viral infection (molecules on viral surface mimic molecules on outside of B cells)
What is the aetiology of type 2 diabetes?
- reduced tissue sensitivity to insulin (insulin resistance)
- inability to secrete very high levels of insulin
What is a major risk factor for type 2 diabetes?
- expanded upper body visceral fat (pot belly)
- also called central adiposity, which is how men and woman after menopause put on weight
What does central adiposity occur due to?
- increased intake of food
- lack of exercise
- genes relatively unimportant
How does pot belly lead to type 2 diabetes?
- increased free fatty acids in blood
- decreases insulin receptor sensitivity
- more insulin is needed to get same amount of glucose into cells
- pancreas reaches point where cannot secrete enough insulin
What does central adiposity lead to?
Hyperinsulinaemia
What are the genetic risks to get type 2 diabetes?
- multiple genes involved in causing inadequate “high level” insulin secretion by B cells
- not HLA genes
- not adiposity genes
What is the link between a gene variant of B cells and type 2 diabetes?
- if gene is a variant it may promote insulin production at low levels but not high levels
- so implicated genes are for poor B cell ‘high end’ insulin secretion
- if have FEW abnormal genes can still produce lots of insulin
In type 1 and type 2 diabetes is anything wrong with insulin receptors?
Type 1
- nothing wrong with receptor
- destruction of B cells
- decreased insulin production
Type 2
- problem with receptors
- decreased insulin sensitivity
- occurs because central adiposity causes receptor complex to not work so insulin cannot bind tightly
What is the annual mortality of people with diabetes?
5.4%, double what people with no diabetes is
How does life expectancy change due to diabetes?
- decreased by 5-10 years
- this is not accurate as there are two groups:
well managed and not well managed
What is the commonest cause of death for people with diabetes?
Myocardial infarction
What do long term complications in diabetes occur due to?
Prolonged poor glycaemic control
What is the main complication in diabetes?
Damage to vessels:
- macrovascular complications
- microvascular complications
What is a macrovascular complication of diabetes?
Accelerates atherosclerosis (does not cause it but accelerates it)
What mechanism explains diabetes accelerating atherosclerosis?
- glucose attaches to LDL (low density lipoprotein) due to more than normal levels
- glucose molecules stop LDL from binding to its receptor on liver cells tightly
- LDL is not removed and stays in blood, causing hyperlipidaemia -> atherosclerosis
What is a microvascular complication of diabetes in arterioles?
- molecules flux into subendothelial space but find it hard to flux back to blood
- build up of trapped molecules under endothelial cells
- basal lamina becomes thickened
Where do microvascular complications due to diabetes (in arterioles) often occur?
Kidneys, peripheral tissues (foot), eyes and arterioles supplying nerves
What are microvascular complications of diabetes in capillaries?
Collagen glycosylation
Cross linked proteins
What is the mechanism of collagen glycosylation?
glucose added to proteins = glycosylation
- non-enzymaticic
- reversible at first
- irreversible if covalent bonds form = advanded glycosylation end products (AGEs)
1. collagen is glycosylated - collagen is in normal basal lamina
- albumin can sometimes get into subendothelial space
2. glycosylated collagen binds to albumin causing accumulation
<em>albumin does not normally combine with collagen and fluxes out of space with no accumulation</em>
What is the mechanism of cross linked proteins?
<em>many normal basal lamina proteins do not cross link and can be removed easily</em>
- glycosylated proteins bind their neighbouring proteins = rigid, crosslinked proteins cannot easily be removed
- persistence of protein in arteriole wall
What is arteriolar disease also called?
Hyaline change
What does hyaline change cause?
Narrows arteriole causing poor blood flow and then ischaemia
Is microvascular and macrovascular damage reversible?
- typically irreversible
- can stop decline if achieve good glycaemic control
