Consequences of hyperglycaemia Flashcards
What are the long term complications of diabetes mellitus (both type 1 and 2) predominantly the result of?
The long term complications of diabetes relate to the severity and duration of hyperglycaemia… NOT the type of diabetes mellitus
The pathology that eventuates is the result hyperglycaemic effects on:
- macrovascular changes
- microvascular changes; or
-
celllular (non-vascular) changes
- Neutrophil dysfunction
- Peripheral nerves
- Hepatocytes
Outline the macrovascular effects incurred by diabetes
ATHEROMA
Atheromas are accelerated in their progression and more severe in diabetic patients
- Atheromas develop in the same places and lead to the same sequelae as normal atheromas, but…
- Diabetics have 10x risk of MI, strokes and angina compared with peers
The atheromas are macroscopically and histologically indistinguishable from non-diabetic atheromas - but occur to more severe extent
This is a result of:
- 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 DM including hyperlipidaemia and hypertension
Macrovascular consequences are the largest cause of death in diabetic patients
Outline the microvascular complications of hyperglycaemia
Microvascular complications relate to the long term effects of hyperglycaemia on cells and extracellular matrix
This primarily occurs via the glycosylation of proteins by glucose:
- Initially labile (Schiff bases)
- Later stabile (Advance glycation end products)
This leads to diabetic patients with a greater risk of developing:
- Diabetic nephropathy
- Diabetic retinopathy
- Diabetic neuropathy; and/or
- **Poor wound healing **
Explain diabetic nephropathy in the context of diabetes
Diabetic nephropathy initially present with **proteinuria **before progressive decline in renal function to a state of chronic renal failure
Diabetic nephropathy is now the most common cause of End Stage Kidney Disease (32%)
**Diabetic nephropathy **encompasses a number of pathological processes within the kidney resulting from hyperglycaemia:
1. Diabetic Glomerulosclerosis / arteriolosclerosis
- Arteriole walls of glomeruli are thickened by the deposition of glycosylated proteins = a form of hyaline arteriolosclerosis
- reduces perfusion to glomeruli and induces sufficient ischemia to cause scarring of the kidneys.
- Histologically see Kimmenstiel-Wilson Nodules that are essentially balls of collagen due to pronounced thinckening of arterioles.
-
Thickening of the basement membrane of glomeruli capillary loops with glycosylated proteins
- alters the charge and function of the basement membrane and become permeable to proteins = proteinuria
_2. Accelerated atheroslerosis in renal arteries _
- greater risk of renal infarcts
_3. _Pyelonephritis
- Hyperglycaemia affect the function of immune cells in the kidney -> greater risk of infection
4. Papillary Necrosis
- Necrosis of kidney medullary pyramids and sloughing off cells
Explain diabetic retinopathy
Results from ischaemia due following microvascular injury (thickening of the vascular wall due deposition of glycosylated proteins) and reduced perfusion to the retina.
Vascular proliferation in retinopathy is a response to the ischemia
Explain the poor wound healing associated with diabetic hyperglycaemia
Poor wound healing results from the multi-factorial influence of hyperglycaemia:
- microvascular injury (hyaline arteriolosclerosis)
- **macrovascular atheroma **
-
increased susceptibility to infection
* due to impaired immune cells - Neuropathy
Foot care is a critical part of DM management as patients will present with:
- constant minor trauma
- impaired healing leading to chronic foot ulcers
- susceptibility to infection
- gangrene
What are Advanced Glycation End Products (AGEs)?
AGEs result from interactions between molecules derived from glucose and the amino groups of various proteins (either inside and outside cells)
They form normally, but the rate of formation elevates significantly in hyperglycaemia beyond the body’s ability to clear them. Diet is a principal source of AGEs in normal individuals as well as those with diabetes mellitus.
Hyperglycaemia -> labile Schiff Bases -> stable AGEs -> glycosylation
How do AGEs mediate organ damage in hyperglycaemia?
There are two pathways by which AGEs can cause effects:
RAGE
The AGEs bind to a specific receptor (RAGE) on inflammatory cells (including macrophages and T cells), endothelial cells, and vascular smooth muscle
Activation of RAGE leads to:
- release of pro-inflammatory cytokines and growth factors from macrophages
- Generation of reactive oxygen species in endothelial cells
- Increased pro-coagulant activity in endothelial cells (disrupts thrombosis + contributes to atheroma)
- **Proliferation and matrix production by vascular smooth muscle **cells (may contribute to atheroma formation)
Cross-linking effects (non-receptor mediated)
AGEs can cross link extracellular matrix
proteins
- Cross linking Type I collagen in vessel walls alters their dynamics and can lead to vessel injury
- AGE-induced cross linking of Col IV in basement membranes alters attachment of endothelium and alters permeability; also thicken basement membrane
- Cross linked proteins are resistant to degredation
- AGE bound-membrane components can trap other proteins like LDL -> possible explanation of accelerate atheroma formation
Other than the AGEs, list the other pathways through which hyperglycaemia causes pathology
- Activation of Protein Kinase C
- Abnormal Polyol Pathways
Explain how peripheral neuropathy develops in hyperglycaemia
Peripheral neuropathy is a significant problem
in longstanding DM
It was original thought to be a vascular problem supplying the neurons but this has changed. It is now though to be a result of the combined effects of:
- AGE-related damage leading to loss of axons
- Possibly Polyol-related damage
- Microvascular injury (arterioles) leading to neuronal ischaemia
Peripheral neuropathy manifests as:
- numbness
- autonomic depression
- impotence
- etc
How does Non-Alcoholic Steatohepatitis result from hyperglycaemia?
Its not certain whether NASH is a consequence of DM - perhaps better thought of as an association.
NASH is characterised by:
- fat accumulating in liver cells
- Infiltrate of neutrophils and lymphocytes that result in liver cell damage
- Hepatic fibrosis
The pathogenesis is still unclear; but the hypothesis involves:
- Alterations to normal balance of lipid delivery to theliver, lipid synthesis in liver, and lipid packaging and export
- abnormal insulin related lipolysis, insulin activation of lipid synthesis in liver, and others
NASH is independently associated with obesity, insulin resistance and hyperglycaemia
