Pathogenesis of Micro and Macrovascular

Complications of Diabetes
Macrovascular Complications
Macrovascular complications are due
accelerated atherosclerosis, as
diabetes is a major risk factor for this due
to hyperlipidaemia caused by low insulin
levels.
Involves inflammatory processes including
the release of inflammatory mediators. Endothelial cell dysfunction occurs early on in
the pathology of atherosclerosis.

Microvascular Complications
The cause of microvascular complications
are unclear but it thought to be similar to
those of macrovascular, and instead is due
to hyaline arteriolosclerosis
characterised by thickening of the vessel
wall and basement membrane. Vessel
lumen is reduced causing localised
ischaemia. The role of hyperglycaemia plays
a role in predisposing to macrovascular
disease but it is critical in the development
of microvascular disease.
Factors associated with pathogenesis of
microvascular complications:
Hyperglycaemia
Advanced glycation end-products
Reactive oxygen species
Activation of the transcription factor
NFB
Sorbitol accumulation in cells
Activation of cell protein kinase C
Haemodynamic changes

Consequences of Hyperglycaemia (mechanisms of damage)

Non-enzymatic glycosylation

other
can

Glucose and
glycated
compounds
react with
proteins

(e.g.

haemoglobin, collagen, LDL, and tubulin) and nucleic acids to give glycated
products
This process occurs in peripheral nerves
Glycation occurs in various stages, firstly to give rise to early reversible products
then progress to form advanced glycation end-products (AGEs)
Long term modification of proteins by non-enzymatic glycation and oxidation
results in accumulation of AGEs, causing inflammation via stimulation of proinflammatory factors e.g. complement, cytokines
AGEs modify the function of proteins by affecting:
o Intracellular proteins by altering function
o Extracellular matrix proteins, leading to abnormal interactions with other
matrix elements and with matrix receptors
o Plasma proteins by causing binding to and activation of macrophages
Levels of tissue AGEs increases with age and can be derived from exogenous
sources e.g. food and tobacco smoke

Reactive oxygen species

Increased production of reactive oxygen species causes reduced availability
of nitric oxide
Nitric oxide is a mediator that is normally produced by endothelial cells to
maintain vascular homeostasis
With reduced NO, it leads to a loss of its anti-inflammatory, Antiproliferative
and anti-adhesive properties and an increases in proinflammatory factors
Activation of NFB
NFB is an intracellular transcription factor that mediates proinflammatory
responses
Activation of NFB can result from oxidative stress and from binding of AGEs to
cell receptors on cells e.g. macrophages
Activation promotes vasoconstriction and expression of proinflammatory
cytokines and procoagulants
Polyol pathway

Polyol pathway refers to the enzyme

aldose reductase
Its function is to normally reduce
toxic aldehydes in the cell to inactive
alcohols but if glucose concentration
in the cell is too high, aldose
reductase reduces glucose to
sorbitol, which is later oxidised to
fructose
o Sorbitol is produced from
glucose and NADPH via action
of aldose reductase
Sorbitol accumulation can cause a fluid imbalance within the cells, leading to
disruption of cellular osmoregulation and cell function
Accumulation of sorbitol inside cells e.g. nerve or renal cells damages the cells

Activation of protein kinase C (PKC)

Hyperglycaemia
inside the cell
increases the
synthesis of a
molecule known as
dicylglycerol
It is a critical
activating cofactor for
isoforms of protein
kinase-C, -, -, and
-.
Accumulation of
diclyglycerol occurs in diabetes and causes excessive PKC activation
PKC normally regulates vascular permeability, contractility and proliferation
Excessive PKC activation however also means that vascular endothelial
growth factor 1 (VEGF-1) is produced in excess too, which is a prime culprit
in diabetic eye disease
Transforming growth factor- is known to cause changes in vascular
permeability
Abnormal microvascular blood flow
Impairs the supply of nutrients and oxygen
Vasoconstrictors e.g. endothelins and thrombogenesis are responsible for
microvascular occlusion, leading to endothelial damage
Haemodynamic changes
Particularly affecting eyes and kidney
Increased blood viscosity
Increased shear stress

Plugging of capillaries by activated leukocytes

Closure of capillaries
Proliferation of new vessels (in chronic hypoxia)

References:
1. Kumar and Clarke Clinical Medicine pg. 1021
2. Endocrinology Crash Course 4th Edition
3. An Illustrated Coloured Text Endocrinology
4. http://diabetes.diabetesjournals.org/content/54/6/1615.full