Retina Diabetic Retinopathy Companion Note

Diabetic Retinopathy: Why the Retina Leaks and Becomes Ischaemic

Understand how persistent hyperglycaemia injures the retinal neurovascular unit and produces the two central processes of diabetic retinopathy: vascular leakage and capillary non-perfusion.

Learner level Foundation to early postgraduate

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Watch the lecture first, or use the companion note below to revise how hyperglycaemia leads to retinal leakage, non-perfusion and neovascularisation.

The Path from Hyperglycaemia to Retinopathy

Cumulative hyperglycaemic exposure

Metabolic, oxidative and inflammatory stress

Retinal capillary injury

Vascular leakage or capillary non-perfusion

Clinical diabetic retinopathy

Leakage

Capillary-wall injury and barrier breakdown microaneurysms, retinal haemorrhages, hard exudation and diabetic macular oedema

Non-perfusion

Capillary closure and dropout retinal ischaemia, VEGF release and neovascularisation

Duration Creates Cumulative Risk

The risk of diabetic retinopathy rises with the duration of diabetes and cumulative glycaemic exposure.

Important risk modifiers

Long-term glycaemic control
Hypertension
Diabetic kidney disease
Dyslipidaemia
Pregnancy in patients with pre-existing diabetes

Better glycaemic and blood-pressure control reduces the development and progression of diabetic retinopathy. [1] [6] [7]

Historical estimates

Classic epidemiological teaching suggested that after approximately 20 years of diabetes, nearly 99% of people with type 1 diabetes and more than 60% of those with type 2 diabetes had developed some degree of retinopathy.

These are historical estimates from older cohorts; the younger-onset Wisconsin cohort reported retinopathy in approximately 97.5% after 15 years or more. [2] [3]

Contemporary estimates

Contemporary estimates are lower and more variable. One type 1 diabetes cohort reported retinopathy in approximately 54% at 20 years, while a modern type 2 diabetes cohort reported approximately 53% prevalence at 20–25 years.

Rates vary between populations, treatment eras and screening methods. [4] [5]

Hyperglycaemia Creates Metabolic Stress

Persistent hyperglycaemia activates several interacting biochemical pathways that converge on oxidative stress, inflammation and retinal neurovascular dysfunction. [8] [9] [10]

Polyol Pathway

Excess intracellular glucose is converted to sorbitol by aldose reductase, using NADPH.

NADPH is also required to regenerate reduced glutathione, an important intracellular antioxidant. Excessive NADPH consumption therefore reduces glutathione-dependent antioxidant capacity.

Sorbitol is then converted to fructose by sorbitol dehydrogenase, using NAD⁺ and producing NADH.

Sorbitol oxidation therefore increases the intracellular NADH:NAD⁺ ratio, producing redox imbalance and potentially increasing reactive oxygen species generation.

Sorbitol accumulation Osmotic stress

NADPH depletion Reduced antioxidant defence

Increased NADH:NAD⁺ ratio Redox imbalance

[8] [9]

Advanced Glycation

Glycation is the non-enzymatic attachment of reducing sugars to proteins, lipids or nucleic acids.

With persistent hyperglycaemia, these early glycation products undergo further modification to form advanced glycation end products (AGEs).

AGEs alter proteins and extracellular matrix and can activate the receptor for advanced glycation end products (RAGE).

AGE–RAGE signalling promotes:

Oxidative stress
Inflammation
Endothelial dysfunction
Abnormal extracellular-matrix turnover
Leukocyte adhesion

[8] [9]

Other Hyperglycaemic Pathways

Hyperglycaemia also activates:

Protein kinase C
The hexosamine biosynthetic pathway
Mitochondrial production of reactive oxygen species

These pathways further disturb vascular permeability, blood-flow regulation, inflammatory signalling and extracellular-matrix metabolism.

The hexosamine pathway is distinct from the pentose-phosphate pathway. [8] [9]

From Metabolic Stress to Capillary Injury

Metabolic, oxidative and inflammatory stress damages the principal components of the retinal capillary wall.

Pericyte Loss

Pericytes provide structural support, regulate capillary tone and help maintain endothelial stability. Their loss weakens the capillary wall and contributes to microaneurysm formation.

Endothelial Dysfunction

Endothelial cells regulate retinal blood flow, vascular permeability and leukocyte interaction. Their tight junctions form the inner blood–retinal barrier; dysfunction therefore contributes to both vascular leakage and capillary non-perfusion.

Basement-Membrane Thickening

Abnormal extracellular-matrix turnover disrupts endothelial–pericyte interaction and impairs capillary function.

Leukostasis

Abnormal adhesion of leukocytes to activated retinal endothelium contributes to endothelial injury, barrier breakdown and impaired capillary perfusion. [9] [10] [11]

Together, these changes lead to the two major pathways of diabetic retinopathy:

Vascular leakage

Capillary non-perfusion

Vascular Leakage

Leakage in diabetic retinopathy reflects two related but distinct consequences of retinal capillary injury: capillary-wall fragility and breakdown of the inner blood–retinal barrier.

Capillary-Wall Damage

Loss of pericyte and endothelial support weakens the retinal capillary wall and makes it structurally unstable.

Capillary-wall fragility Microaneurysms and retinal haemorrhages

Barrier Breakdown

Dysfunction of endothelial tight junctions weakens the inner blood–retinal barrier and increases vascular permeability.

Increased permeability Fluid, plasma proteins and lipoproteins enter the neural retina

Clinical Manifestations

Microaneurysms

Focal outpouchings arising from structurally weakened retinal capillaries.

Retinal haemorrhages

Blood escapes from damaged or fragile retinal microvessels.

Hard exudates

Lipid-rich residues remain after leakage of plasma constituents into the retina.

Diabetic macular oedema

Retinal thickening caused by blood–retinal barrier breakdown and vascular leakage involving the macula.

[1] [9] [10]

Capillary Non-Perfusion and Retinal Ischaemia

Endothelial injury, leukocyte adhesion and progressive capillary degeneration can cause retinal capillaries to close and disappear from the functioning circulation.

Endothelial injury and leukocyte adhesion

Capillary degeneration, closure and dropout

Retinal non-perfusion and ischaemia

Cotton-Wool Spots

Cotton-wool spots are focal accumulations of axoplasmic material caused by interrupted axoplasmic transport in ischaemic regions of the retinal nerve-fibre layer.

Venous Beading

Venous beading describes irregular variation in retinal venous calibre and reflects significant disturbance of the retinal circulation.

IRMA

Intraretinal microvascular abnormalities are abnormal intraretinal vascular channels found beside areas of capillary non-perfusion.

[9] [10] [11]

From Ischaemia to Neovascularisation

When capillary non-perfusion becomes extensive, the ischaemic retina increases production of angiogenic mediators—most importantly vascular endothelial growth factor (VEGF).

Extensive capillary non-perfusion

Retinal ischaemia

Increased VEGF production

Retinal neovascularisation

NVD

Neovascularisation of the disc refers to new vessels arising at or near the optic disc.

NVE

Neovascularisation elsewhere refers to new vessels arising away from the optic disc on the retinal surface.

Proliferative Disease

The presence of NVD or NVE defines proliferative diabetic retinopathy.

Why New Vessels Threaten Vision

Fragile vessels

Neovascular tissue is structurally fragile and may bleed into the pre-retinal space or vitreous cavity.

Fibrovascular proliferation

New vessels grow with accompanying fibrovascular tissue along the retinal and posterior hyaloid surfaces.

Traction

Contraction of fibrovascular tissue can pull on the retina and produce tractional retinal detachment.

[12] [13]

Do Not Confuse: IRMA and Neovascularisation

Both are associated with retinal ischaemia, but they represent different vascular responses and have different implications for disease staging.

Feature	IRMA	Neovascularisation
Full term	Intraretinal microvascular abnormalities	New vessels at the disc or elsewhere
Location	Remain within the retina	Grow on the retinal or optic-disc surface
Mechanism	Remodelling of existing intraretinal vascular channels beside areas of capillary non-perfusion	Angiogenic growth of new vessels in response to retinal ischaemia and increased VEGF
Fluorescein leakage	Usually limited or absent	Typically prominent
Disease significance	Prominent IRMA is a feature of severe non-proliferative diabetic retinopathy; the presence of any IRMA does not automatically establish severe NPDR	NVD or NVE defines proliferative diabetic retinopathy

[1] [9] [13]

From Mechanism to Clinical Sign

The retinal signs of diabetic retinopathy become easier to remember when each is linked to its dominant underlying mechanism.

Dominant process	Underlying event	Common manifestations
Capillary-wall instability	Pericyte loss and endothelial dysfunction weaken the retinal capillary wall	Microaneurysms and retinal haemorrhages
Barrier breakdown	Endothelial tight-junction dysfunction increases vascular permeability	Hard exudates, retinal thickening and diabetic macular oedema
Capillary non-perfusion	Capillary degeneration, closure and dropout produce retinal ischaemia	Cotton-wool spots, venous beading and IRMA
Angiogenic response	Ischaemic retina increases VEGF production	NVD, NVE and proliferative diabetic retinopathy

[1] [9] [10] [11] [12] [13]

Clinical Summary

The pathogenesis of diabetic retinopathy can be consolidated into five connected principles.

Cumulative exposure determines risk

Longer diabetes duration and sustained hyperglycaemic exposure increase the likelihood of retinal injury, although modern outcomes are modified by glycaemic and systemic risk-factor control.

Hyperglycaemia activates interacting injury pathways

Polyol-pathway activity, advanced glycation, protein kinase C, hexosamine-pathway activity and mitochondrial oxidative stress converge on inflammation and retinal neurovascular dysfunction.

Retinal capillary injury has two major outcomes

Pericyte loss, endothelial dysfunction, abnormal extracellular matrix and leukostasis lead to vascular leakage or capillary non-perfusion.

Leakage produces oedema and exudation

Capillary-wall instability produces microaneurysms and retinal haemorrhages, while blood–retinal barrier breakdown produces hard exudates, retinal thickening and diabetic macular oedema.

Non-perfusion produces ischaemia and proliferation

Capillary closure produces retinal ischaemia, which increases VEGF production and may progress to NVD, NVE and proliferative diabetic retinopathy.

References

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