Pathology of Diabetes Mellitus Flashcards
What are the endocrine parts of the pancreas?
Islets of Langerhans
What does 2/3rd of the islets consist of?
B cells
What is the role of beta cells?
Secrete insulin
What are HLA molecules?
Molecules that help T cells recognise self from non-self
What is the pathophysiology of type 1 diabetes?
Cannot distinguish own cells from other cells (autoimmune attack on pancreatic B cells)
This leads to lymphocyte infiltration of islets + destruction of B cells –> decreased insulin
What is involved in the aetiology of T1DM?
Environment - ?chemicals, ?viral infection (molecular mimicry)
Genetic predisposition
What is the aetiology of type 2 diabetes?
- Reduced tissue sensitivity to insulin
- Inability to secrete very high levels of insulin
i.e. failure of the B cells to meet increased demand for insulin
What is it that causes insulin resistance in type 2 diabetics?
Expanded upper body visceral fat mass (due to increased food intake, lack of exercise) –> increased FFA in the blood –> decreased insulin receptor sensitivity to insulin (so need more insulin to get glc into cells)
Why does expanded upper body visceral fat mass lead to more FFA in the blood?
Overweight adipocytes are probably stressed + release FFAs
Why do increased FFA in the blood lead to decreased insulin receptor sensitivity?
FAs interfere with the insulin receptor pathway
Complete the sentence:
The ______ needs to secrete _____ _______ to move glucose into cells in a person with central adiposity
Pancreas
More
Insulin
What does decreased insulin receptor sensitivity ultimately lead to?
Decreased removal of glucose from the blood, insulin levels have to markedly rise to make glucose levels return to normal
Central adiposity leads to what?
Hyperinsulinaemia
If peripheral insulin resistance is present how do we keep glucose levels normal?
If the pancreas is able to compensate and produce more and more insulin (then the patient wont get diabetes)
What type of genes are implicated in type 2 diabetes?
Poor B cell ‘high end’ insulin secretion (i.e. not able to compensate for peripheral insulin resistance and produce vast quantities of insulin)
If a person has central adiposity and many genes promoting high end insulin secretion will they get diabetes?
No
If a person has central adiposity and numerous genes defective for high end insulin secretion, will they get diabetes?
Yes - type 2
Is it a single gene involved in causing inadequate high level insulin secretion?
No - it is multiple genes
So in summary, explain the aetiology of type 2 diabetes
Multiple gene defect of pancreatic B cell insulin production which is unmasked by central adiposity
What is the commonest cause of death in diabetics?
MI
What do the long-term complications of DM result from?
Prolonged poor glycaemic control
What is the main complication of diabetes?
Damage to vessels
What are the macrovascular (large vessel) complications of DM?
DM accelerates atherosclerosis
How is atherosclerosis accelerated in DM?
Glucose attaches to low density lipoprotein
Glucose molecules stop LDL from binding to its receptor on liver cells tightly
LDL not removed by liver cells + stays in blood –> hyperlipidaemia –> atherosclerosis
What kinds of cells line arterioles?
Endothelial which sit on a basal lamina
What exists between the basal lamina and endothelial cells?
Potential space
What can happen in the subendothelial space of arterioles?
Molecules can flux in and out
What lines the basal lamina of arterioles?
Smooth muscle cells
What happens to the arterioles in DM?
Molecules flux into subendothelial space (e.g. albumin, collages) + find it hard to flux back into blood
These molecules build up in the subendothelial space, and the basal lamina thickens
This is also known as hyaline change
Narrow arteriole –> poor BF –> ischaemia
Where is hyaline change most damaging?
Kidneys, peripheral tissues (e.g. feet), eyes, arterioles supplying nerves
What happens in the capillaries of diabetics?
Increased connective tissue around capillaries, e.g. glomerulus in kidney
What are Kimmelstiel-Wilson lesions?
Nodules of connective tissue in the kidney
How does small vessel disease occur in diabetics?
Glucoses added to proteins (glycosylation)
Collagen in the basal lamina is normally in the basal lamina. Albumin normally fluxes in and out the subendothelial space. Normal albumin does not bind to collagen, glycosylated collagen does bind albumin –> accumulation of albumin in the subendothelial space
Many normal basal lamina proteins do not crosslink + can be easily removed but glycosylated proteins bind their neighbouring proteins. Rigid, cross linked proteins cannot be easily removed so there is persistence of proteins in arteriole walls even after return to normoglycemia
Is glycosylation reversible?
At first yes, but irreversible once covalent bonds form = advanced glycosylation end products
