Pathology of Diabetes Mellitus Flashcards
What is the main property of exocrine pancreatic tissue?
Acinus
What is the main property of endocrine pancreatic tissue?
Islets of Langerhans
What type of cells are found in the Islets of Langerhans?
B cells (2/3 of cells in I of L)
What is the function of the B cells in the I of L?
Secrete insulin into blood in capillaries
Give a v basic summary of the effect of insulin on fat tissue
Insulin binds to its receptor and drives glucose from plasma into adipocytes (same with muscle cells etc)
Increased glucose =
increased insulin = increased glucose uptake by cells = decreased glucose in serum
Is there a definite aetiology of type 1 diabetes?
No, not entirely known
Give a gene complex found so far to be a possible aetiology of type 1 DM
HUMAN LEUKOCYTE ANTIGEN (HLA)
What is the normal function of the HLA gene complex?
Encodes the major histocompatibility complex (MHC) proteins in humans = cell-surface proteins responsible for regulation of immune system
What does P Brown say is the function of HLA molecules?
‘Molecules that help T cells recognise self from non-self’
How do HLA molecules malfunction to cause type 1 DM?
Cant distinguish own cells form other cells = autoimmune attack on islet cells in pancreas = lymphocyte infiltration of islets (insulitis) = DESTRUCTION OF B CELLS
Name 3 possible environmental triggers for type 1 DM
Chemicals (pollutants e.g. PCBs, toxicants, air pollutants)
Bacteria altered in gut in infancy
Viral infection (molecules on viral surface mimic molecules on outside of B cells)
What is the general ‘equation’ for aetiology of type 1 DM?
Genes + Environment = Destruction of B cells = Decreased Insulin + increased blood Glc
Is there a definite known aetiology for type 2 DM?
No, not entirely known
What 2 things are the aetiology of type 2 DM thought to be a result of?
- Reduced tissue sensitivity to insulin (insulin resistance)
- Inability to secrete very high levels of insulin
What simple way does P Brown put the aetiology of type 2 DM?
‘A failure of the B cells to meet an increased demand for insulin in the body’
What is an important ‘environmental’ factor in the aetiology of type 2 DM? (I dont rly think this is ‘environmental’ ??)
Expanded upper body visceral fat mass (‘pot belly’)
Are genes associated with expanded upper body visceral fat mass?
No, genes are relatively unimportant - usually due to increased intake of food and lack of exercise
How does expanded upper body visceral fat mass affect blood content?
Results in increased free fatty acids in blood
Why does pot belly increase free fatty acids in blood?
Overweight adipocytes are ‘stressed’ and so release fatty acids
What effect do increased free fatty acids have on insulin receptors?
They decrease insulin receptor sensitivity
Why do free fatty acids decrease insulin receptor sensitivity?
Unclear
Describe how the body copes with peripheral insulin resistance caused by central adiposity
Decreased insulin receptor sensitivity, so pancreas now needs to secrete more insulin to get normal amount of glucose into cells = hyperinsulinaemia
Does the fact that central adiposity causes hyperinsulinaemia and peripheral insulin resistance mean that these people have diabetes?
No, people might not yet be diabetic; diabetes will occur if insulin increases substantially
So if central adiposity does not necessarily cause type 2 DM, what factor when added to the central adiposity can cause it?
Genetics
Describe how some genes can lead to type 2 DM
Gene variants which can control whether you secrete large amounts of insulin or not
How do these gene variants impact insulin levels?
Gene may promote insulin production at low levels but NOT high levels; implicated genes are for poor B cell ‘high end’ insulin secretion
What is the difference between having a few of these abnormal gene variants and having many of these gene variants?
Only a few genes abnormal means will be able to secrete lots of insulin to compensate whereas having many gene variants for lower insulin production means you CANT produce large amounts of insulin
So summarise in concise, simple terms what occurs to cause type 2 DM
In type 2 diabetes, insulin secretion does not increase enough to counteract insulin resistance caused by central adiposity
Are there oddities in the development of type 2 diabetes?
Yes, a slim person who puts on small amount of weight may get type 2 if they have v high dosage of lower insulin genes; vice versa with an overweight person with v good genes
Are HLA genes or adiposity genes involved in development of type 2 DM?
NO
Define type 2 diabetes (according to Paul)
A multiple gene defect of pancreatic B cell insulin production which is unmasked by central adiposity
By how much is life expectancy reduced for diabetics?
5-10 yrs
What is the most common cause of death for diabetics?
Myocardial infarction
Are the long term complications of DM dependent on the cause?
no, occur regardless of cause
What do long term complications of DM result from?
prolonged poor glycaemic control (5-10 yrs)
What is the main complication of DM
Vessel disease (large - arteries; small - arterioles/capillaries)
What does DM cause in large vessels?
Acceleration of atherosclerosis
Describe one proposed mechanism of how DM causes atherosclerosis
Glucose molecules attach to LDL; stop it binding to its receptors tightly; LDL is therefore not removed by e.g. liver cells and stays in the blood = hyperlipidaemia = atherosclerosis
Describe the structure of arterioles (3 ‘layers’)
Endothelial lining cells make basal lamina (collagens) so sit on and creates a potential subendothelial space between endothelial cells and lamina; around lamina are smooth muscle cells
Describe the movement of molecules in and out of the subendothelial space in arterioles in DM
Molecules flux into subendothelial space but find it hard to flux back to blood
In DM arterioles, molecules have difficulty fluxing back into blood, what does this result in?
Build up of ‘trapped’ molecules under endothelial cell and thickening of basal lamina
What type of molecules accumulate in subendothelial space of arterioles?
Plasma proteins (e.g. albumin) Connective tissue (e.g. collagens)
What is arteriolar disease also called?
Hyaline change
What does this thickening of lamina result in in arterioles?
Narrow arteriole = Poor blood flow = Ischaemia
Where does arteriolar disease/hylaine change particularly damage in the body?
Kidney
Peripheral tissues (foot)
Eyes
Arterioles supplying nerves
What is there an increased morbidity for as a result of arteriolar disease in DM?
Amputation 40x
End stage renal disease 25x
Blindness 20x
What is there a higher risk of developing as a result of atherosclerosis as a result of DM?
Coronary heart disease 2-20x
Myocardial infarction 2-5x
Atherothrombotic stroke 2-3x
What change occurs in small vessels (capillaries) as a result of DM?
Increased connective tissue around capillaries e.g. glomerulus in kidney
What is the name for a nodule of connective tissue in capillary?
Kimmelstiel-Wilson
Give one mechanism for how small vessel disease occurs in DM
Glucose added to proteins (= glycosylation)
Give some properties of glycosylation in small vessel disease
Non-enzymatic
Reversible at first
Irreversible if covalent bonds = Advanced Glycosylation End-products (AGEs)
Give an example of glycosylation products in small vessels
Collagen is glycosylated; albumin fluxing out of cell will bind to glycosylated collagen (will not bind to it when not glycosylated); results in accumulation of albumin subendothelial space
Give another example of glycosylation products in small vessels
Normal basal lamina proteins dont crosslink and can be removed easily, but glycosylated proteins bind to their neighbours and become rigid (cant be easily removed), and persist even in normoglycaemia
Glycosylation in capillaries =
accumulation of TRAPPED plasma proteins + accumulation of CROSS-LINKED basal lamina proteins
Is large + small vessel disease in DM typically reversible or irreversible?
Irreversible when established
What setting does large + small vessel disease in DM usually occur?
Prolonged, poor diabetic control
