The Pathology of Diabetes Flashcards
What does diabetes strictly refer to?
Abundant production of urine
What does diabetes mellitus mean?
Polyuria secondary to glycosuria because of hyperglycaemia
Is diabetes a single pathology?
No, it’s a group of conditions
Endpoint = chronic hyperglycaemia
Where is insulin produced?
Beta cells in pancreatic islets
How do insulin levels rise?
After meal > increased blood glucose
What does insulin do?
Promotes glucose uptake and utilisation in tissues
Which tissues have a high expression of the insulin receptor?
Adipose tissue
Muscle
Liver
What is the structure of the insulin receptor?
Tetramer
- 2 alpha subunits - extracellular
- 2 beta subunits - intracellular
What does insulin binding to the insulin receptor lead to?
Tyrosine phosphorylation of substrate proteins
Translocation of glucose transport proteins to surface
Alteration to lipid and glucose metabolism
What does acute hyperglycaemia in type 1 diabetes cause?
Produce ketones > acidosis
Hyperglycaemia
Worsening dehydration
Leads to diabetic ketoacidosis
What does acute hyperglycaemia in type 2 diabetes cause?
Severe hyperglycaemia
Increasing serum osmolarity
Lapse into hyperosmolar coma
What do the consequences of diabetes relate to?
Severity
Duration
Which organs do major changes in diabetes involve?
Blood vessels
- Macrovascular = larger muscular and elastic arteries
- Microvascular = capillaries and arterioles
What are the macrovascular effects of diabetes?
Atherosclerosis
What is the rate of progression and severity of atherosclerosis in diabetes?
Accelerated and more severe
Where do diabetic patients develop atherosclerosis?
Usual areas
- Coronary arteries
- Carotid arteries
- Aorta
- Iliac arteries
What is the risk for cardiovascular events in type 1 diabetics compared to age-matched non-diabetics?
10 times higher
How can you tell atherosclerosis apart in diabetics and non-diabetics?
Macroscopically and histologically indistinguishable
What are some of the factors that contribute to atherosclerosis in diabetics?
Increased hepatic production of atherogenic lipoproteins
Suppression of lipid uptake in peripheral tissues
Abnormal endothelial function with pro-coagulant results
Associated abnormalities frequently seen in diabetes including
- Hyperlipidaemia
- Hypertension
What are the consequences of atherosclerosis?
Myocardial infarction
Thrombotic stroke
Infarcts in peripheral tissues; eg: toes
In diabetics, what type of strokes are more common?
Infarcts
Which vessels are part of microvascular beds?
Arterioles - particularly susceptible to disease processes
Capillaries
What are the microvascular effects of diabetes?
Kidney > diabetic nephropathy
Retina > diabetic retinopathy
Delayed wound healing
Foot ulcers
What do microvascular complications of diabetes relate to?
Long term effects of hyperglycaemia on cells and extracellular matrix
Especially glycosylation of proteins
What effect does glycosylation have on the proteins?
Don’t break down/break down slowly
What do glycosylated proteins look like in a H&E stain?
Pink
Thick
Acellular
What are Schiff bases?
Initially reversible glycosylated proteins
What are advanced glycation end products?
Later stable glycosylated proteins
How can you decrease the risk of microvascular complications?
Tight glycaemic control
What is the pathophysiology of diabetic nephropathy?
Glomerulus walls become thicker > more leaky > proteinuria
Much later > renal failure
What is often the initial presentation of diabetic nephropathy?
Proteinuria
What can you need if you have chronic renal failure?
Dialysis
Transplant
What problems in the kidney does diabetic nephropathy cause?
Diabetic glomerulosclerosis/arteriolosclerosis
Infection - also because of affected neutrophil function
Papillary necrosis
Accelerated atherosclerosis in larger arteries
What is diabetic glomerulosclerosis?
Glycosylated proteins embedded in walls of glomeruli > leakiness
What do kidneys look like macroscopically in late stage diabetic nephropathy?
Scarred Pale Shrunken Granular Impaired function
What do the lesions in diabetic nephropathy look like histologically?
Kimmelstiel-Wilson nodules = spherical nodules in mesangium > become balls of collagen
Hyaline arteriolosclerosis = arteriolar wall thickening by acellular proteinaceous material
What does the glomerular basement membrane in diabetic nephropathy look like under the electron microscope?
Thickened
What is the most common cause of end stage kidney disease?
Diabetic nephropathy
How common is diabetic retinopathy?
Occurs to some degree in up to 80% of diabetics after 20 years
What is the primary pathological process in diabetic retinopathy?
Ischaemia because of microvascular injury and reduced perfusion
Why does vascular proliferation in diabetic retinopathy occur?
In response to ischaemia
Are the changes of diabetic retinopathy visible with an ophthalmoscope?
Yes
Why is there slower wound healing in diabetes?
Impaired perfusion because of microvascular injury Also partly because of - Macrovascular disease - Increased susceptibility to infection - Possible neuropathy
Why are foot ulcers difficult to treat in diabetes?
Poor wound healing
Difficulty eradication infection
Neuropathy
Leads to repeated minor trauma
What is often the only option in treating foot ulcers in diabetes, so that the person is able to return to a mobile, active life?
Amputation
What is the problem with amputation as a treatment for foot ulcers in diabetes?
Creates wound on stump > slow to heal
What is a critical part of management in diabetes?
Foot care
Why is chronic hyperglycaemia damaging to tissue?
3 possible metabolic pathways, unclear which is more important
- Advanced glycation end products
- Activation of protein kinase C
- Intracellular hyperglycaemia and abnormal polyol pathways
What are advanced glycation end products?
Reactions between molecules derived from glucose and amino groups of proteins inside and outside cells
Are advanced glycation end products possible in people without diabetes? If so, how are they different in people with diabetes?
Yes, form normally, but rate of formation shoots up in hyperglycaemia
What do the advanced glycation end products do?
Bind to receptor = RAGE
Where is the RAGE receptor located?
Inflammatory cells - Macrophages - T cells Endothelial cells Vascular smooth muscle
What is the principle source of advanced glycation end products?
Diet
When are advanced glycation end products associated with organ damage?
Levels become high and remain chronically increased like in diabetes and ageing
What do high levels of advanced glycated end products lead to?
Release of pro-inflammatory cytokines and growth factors from macrophages
Generation of ROS in endothelial cells
Increased pro-coagulant activity in endothelial cells
Proliferation and matrix production by vascular smooth muscle cells
What are the effects of advanced glycated end products not mediated by RAGE?
Cross link extracellular matrix proteins
- Cross link type I collagen in vessel walls > alters dynamics > vessel injury
- Cross linking of type IV collagen in basement membranes > alters attachment of endothelium and permeability > thickens basement membrane
Why are proteins cross linked because of advanced glycated end products a problem?
Resistant to degradation
Advanced glycated end product-bound matrix proteins trap other proteins including LDL > possible explanation for accelerated atherosclerosis
What activates protein kinace C in intracellular hyperglycaemia?
2nd messenger = diacyl glycerol (DAG)
Intracellular hyperglycaemia stimulates overproduction
What does protein kinase C activation lead to?
Pro-angiogenic growth factors; eg: VEGF
Elevated endothelin-1 and reduced NO > tendency to small vessel constriction
Pro-fibrogenic growth factors; eg: TGF-beta > increased production of basement membrane and matrix
Pro-inflammatory cytokines from endothelium
Do tissues without insulin receptors have higher intracellular glucose concentrations with persisting hyperglycaemia?
Yes
How is excess intracellular glucose metabolised?
Through intermediates = polyols > to fructose
What molecule does polyol metabolism use up?
Glutathione
What is glutathione needed for?
Protects cells againt oxidative stress
What happens to glutathione levels, and what are the consequences, in sustained elevated intracellular glucose?
Reduction in available glutathione > cells vulnerable to oxidative stress
What pathology could be more likely to happen because of increased polyol metabolism in diabetes?
Diabetic neuropathy
What contributes to peripheral neuropathy in diabetes?
Advanced glycated end product-related damage > loss of axons
Possibly polyol related damage
Microvascular injury > neuronal ischaemia
What is non-alcoholic steatohepatitis (NASH) associated with?
Obesity
Dyslipidaemia
Hyperinsulinaemia and insulin resistance
Overt T2D
What happens in NASH?
Fat accumulates in liver cells
Infiltrate of neutrophils and lymphocytes
Liver cell damage
Eventually fibrosis
Is NASH a consequence of diabetes?
Not clear if consequence
Right now considered close association
How can you divide the complications of diabetes into three categories?
Macrovascular/atherosclerosis Microvascular Cellular (non-vascular) - Neutrophil dysfunction - Peripheral nerves - Hepatocytes - CNS cell populations; eg: dementia - Others
