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WOUND HEALING AND DIABETES
THE 5 COMPONENTS OF DIABETES
1. Deficient insulin action:
 decreased production (type 1)
 increased peripheral resistance (type 2)
2. Increased glucagon action.
3. Chemical alterations:
 CHO, protein, lipid.
4. Altered body compartment fluids affecting hydration & osmolality.
5. Organ alterations
 primary: eg, pancreatic islet cells
 secondary: angiopathy, neuropathy, nephropathy, retinopathy, etc.
IMPAIRMENT OF WOUND HEALING IN DIABETICS
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Cell damage results from
1. nonenzymatic glycation of intra/extracellular proteins forming Advanced
glycosylation endproducts (AGEs)
o Protein-bound AGEs, for example, contribute to a variety of pathological
effects - acute changes in protein function and chronic changes in gene
expression. i.e acting to increase vascular permeability, enhance
subintimal protein and lipoprotein deposition, and exert direct toxic
effects on endothelial cells.
o Glycosylation of collagen (less stable), increased collagenase activity
o Associated with increased permeability of proteins across blood-nerve
barrier: Accumulation in nerve
2. increased polyol pathway activity
o glucose is converted to sorbitol and fructose by the enzymes aldose
reductase and sorbitol dehydrogenase.
o leads to swelling of peripheral nerves and therefore risk of chronic nerve
compression
3. increased formation of reactive oxygen species.
o In cells not requiring insulin for glucose uptake (e.g. Schwann cells, lens
of eye), hyperglycemia leads to metabolism of excess glucose -> excessive
glucose metabolites (e.g. sorbitol) with reduced synthesis of an important
antioxidant -> osmotic cell injury and increased susceptibility to oxidative
injury (oxidative stress)
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Due to
1. Local ischaemia
i. Macroangiopathy
ii. Microangiopathy (this is now thought not to be a factor)
iii. Haemorheological changes
2. Neuropathy
i. Motor
ii. Sensory
iii. Autonomic
3. Immune changes
i. Cellular
ii. Humoral
4. Propensity to Infection
LOCAL ISCHAEMIA
Microangiopathy
 Traditionally believed to be important largely because of a non blinded, retrospective
study by Goldenberg. He examined amputation specimens with PAS stain, noted an
increased amount of stain in the arteriolar walls of diabetics and concluded that
microangiopathy is important in the development of their secondary ischaemic changes.
 Subsequently, a number of studies have contradicted Goldenberg's findings and Morain's
conclusions were that:
1. large arterial disease is important (because surgically correctable), and
2. significant functional ischaemia occurs due to haemorheological changes.
Macrovascular
 Associated hypertension and hyperlipidemia
 Advanced gycosylation endproducts acting to increase vascular permeability, enhance
subintimal protein and lipoprotein deposition, and exert direct toxic effects on endothelial
cells.
Haemorheological changes
 Spectrin is a RBC membrane protein.
 Hyperglycaemia causes non enzymatic glycosylation of spectrin. This affects the RBC
membrane, causing it to become stiff and non deformable resulting in:
a) possible microvascular endothelial damage,
b) RBC agglutination
c) increase in blood viscosity.
 According to Poiseuille's law, microvascular flow is related to:
i. hydrostatic pressure,
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ii. vessel lumen diameter to the power 4,
iii. blood viscosity,
 viscosity is related to:
a) RBC rigidity,
b) RBC agglutination.
As viscosity increases, so hydrostatic pressure needs to increase to maintain flow. This leads
to marked transudation which further increases viscosity due to haemoconcentration and also
leads to interstitial oedema and worsened oxygen delivery to the tissues.
The THIXOTROPIC nature of blood:
 Blood at rest - gel like
 Blood in motion - liquid.
ie, as flow slows so viscosity increases - vicious circle which results in very sluggish flow in
some parts of the microcirculation.
ie, a functional ischaemia.
WHAT CAN WE DO ABOUT IT?
1. Tight metabolic control of diabetes.
 Normoglycaemia returns spectrin to normal in 24 hours.
 Shifts Hb dissociation curve to allow optimal tissue oxygen delivery.
2. Bed rest.
 Decreases hydrostatic pressure, transudation and oedema in the legs and therefore
improves oxygen delivery.
3. Pentoxifylline
 Reduces blood viscosity - appears to be related to erythrocyte adenosine
triphosphate (ATP) concentrations and the phosphorylation of erythrocyte
membrane proteins, both mechanisms resulting in an improvement in erythrocyte
flexibility
 Studies show improvement in walking distance, paresthesia, skin temperature,
and subjective overall response.
2. NEUROPATHY
Due to:
1. neuroischaemia
2. alterations in endoneurial flow.
3. Intracellular hyperglycemia – free oxygen radicals
4. nerve oedema – prone to compression
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Effect:
 Sensory neuropathy - failure of early warning system.
 Motor neuropathy - alteration of pressure points.
The overall effect of neuropathy in causing poor wound healing in diabetics is considered by
some to be a more important factor than local ischaemia.
3. IMMUNE CHANGES
Changes in cellular immunity
 Neutrophils - Diminished adherence, chemotaxis, phagocytosis & diapedesis.
 Macrophages - Poorer phagocytosis.
 Lymphocytes - Impaired blast transformation, killing ability, granuloma formation & skin
reactions.
Changes in humoral immunity
 Abnormal opsonic ability.
4. INFECTIONS
 Diabetic surgical patients are at increased risk of infections.
 Infections, when they do occur, are also more severe in diabetics.
 Infections lead to loss of metabolic control.
 Why this increased risk of infection?
1. Impaired defences - skin, mucous membranes.
2. Ischaemia - macro & microvascular, functional.
3. Neuropathy - sensory, motor.
4. Immunological changes - cellular, humoral.
5. Consequence of hyperglycaemia Blood glucose level
Growth on culture
normal - 100 mg/dl
G-ves in 81%
>130 mg/dl
G+ves in 82%
CONCLUSIONS
In diabetics:
1. Infections progress more rapidly.
2. There are defects of wound healing affecting capillary ingrowth, fibroblast
proliferation and collagen synthesis.
3. Leukocyte dysfunction: reduced chemotaxis, phagocytosis, opsonisation.
4. Local hypoglycaemia encourages bacterial growth.