NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19

ID: 1323255

TITLE: Diabetes mellitus: Diabetic Retinopathy and VEGF- Pathophysiology

and Treatments

ABSTRACT

Diabetic Retinopathy (DR) has been recognised as the leading cause of vision

impairment and permanent blindness in middle age and older people of the developed world.

DR is a common microvascular complication which has threatened patients with diabetes

mellitus across the globe. The vascular endothelial growth factor VEGF becomes a well-

known leading factor of DR disease due to its significant role in angiogenesis. Researchers

have viewed VEGF as a critical word for understanding the causes and treatments of DR.

Investigations on DR treatment have grown spectacularly over decades and remain

challenging. The benefits of anti-VEGF in clinical and laboratory practices as debated by

scholars is "imbalance". Multiple studies support that anti-VEGF is a preferable, less

destructive and safer treatment for DR patients. On the other hand, some disagreed due to its

limitations in DR therapy. They discovered that the majority of DR patients, who are injected

with anti-VEGF fail to achieve visual improvement. This paper presents the review of the old

and the new understandings of the pathophysiology in DR associates with VEGF and

discusses various perspectives on the clinical uses of anti-VEGF agents or drugs to treat DR.

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

INTRODUCTION

Diabetes mellitus (DM) is one of the deadly diseases around the globe with profound

morbidity. It is associated with high levels of blood glucose (Hyperglycaemia) which is caused by the

defects in insulin production, insulin action, or both. The DM is characterised by chronic

hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. The common

symptoms of DM include thirst, blurring of vision, polyuria and weight loss. However, Diabetes

mellitus is a global epidemic with its long-term effects known as Retinopathy, kidney failure, foot

ulcers, amputation, Charcot joints, sexual dysfunction and many more. Some studies stated that

Diabetes mellitus leads to two primary complications. They are macrovascular (large blood vessel)

complications and microvascular (small blood vessel) complications. These complications cause

diseases such as cardiovascular disease and nephropathy disease, respectively.

DR is a common microvascular complication of diabetes mellitus (Cheung, Larsern, Sharma,

Simón & Wong, 2016) and is the common causes of eye diseases beside age-related macular

degeneration (AMD) (Chew, 2011) that cause blindness. If the condition is not treated, patients can

result in the abnormal growth of new retinal blood vessels and diabetic macular edema. Therefore,

the exudation and edema in the central part of the retina are induced, and damages retina, which

may lead DR into its worst stage known as proliferative DR. This article review will focus on the

physiology and critical factors of Diabetic Retinopathy (DR) from different perspectives. The

pathophysiological mechanism is commonly activated by hyperglycaemia (High blood sugar) and

hypertension (High blood pressure). This includes many factors, but the major one is the vascular

endothelial growth factor (VEGF). VEFG are a subfamily of growth factors that signal proteins for

both vasculogenesis and angiogenesis. It is becoming one of the significant therapy research in DR

treatment. Likewise, there are recent studies about the treatment of DR, but the most destructive

and safe one is Anti-VEGF therapy.

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

BODY

Prevalence of Diabetic Retinopathy

The prevalence of Diabetic Retinopathy as discussed by Cheung, Larsern, Sharma, Simó and

Wong (2016) occurs in people with either Type1 Diabetes Mellitus (T1DM) or Type2 Diabetes

Mellitus (T2DM). This refers to diabetic patients who have been living a life with diabetes over

decades. The DR is present in approximately 30% of diabetes patients. In many countries, people

with DM at working-age (20-74) are vulnerable to Diabetic Retinopathy, and most of them suffered

from vision loss. However, Cheung, Mitchell and Wong (2010) depict that DR in people with T1DM is

decreasing compared to people with T2DM due to the improvement in diabetes care of T1DM. They

also illustrate that Diabetic Retinopathy starts to develop in people with diabetes after ten years

after diagnosis. The rate of DR is increasing in some countries (e.g., India) due to increased obesity

and changes in the socio-economic conditions. In contrast, developed countries such as the USA,

China, Britain, Australia, as to name some, the DR prevalence rate is decreasing as a result of better

care to a patient with diabetes mellitus. Besides, the rate of prevalence of DR is high in rural areas

such as in China and undeveloped Pacific countries such as Kiribati, Tuvalu, Marshall and others.

The physiological symptoms and signs

The symptoms and signs of Diabetes Retinopathy are characterised by the two main stages

of Diabetic Retinopathy known as non-proliferative Diabetic Retinopathy (NPDR) and proliferative

diabetic Retinopathy (PDR). Wang (2018) discusses that NPDR represents mild Retinopathy, a stage

where an increased vascular permeable and capillary occlusion (blockage in blood vessels) are

beginning to be observed in the retinal vasculature. At this stage, microaneurysms or small circular

deep-red dots in the fundus are revealed through early diagnosis, and patients start to experience

blurred vision, floating spots, changing colour and eyesore (Marco & Veritti, 2011). In contrast, PDR,

as discussed by (Marco & Veritti, 2011) and (Cheung, Larsern, Sharma, Simón & Wong, 2016),

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

represents a severe DR associated with a sudden loss of vision caused by the bleeding of the new

abnormal vessels into the vitreous and the retinal start to detach.

Also, Lo and Wang (2018) argue that the loss of vision in DR patients is commonly caused by

is Diabetic macular edema (DME). It is the swelling or thickening of the macular due to the abnormal

accumulation of fluid, which is induced by the breakdown of the blood-retinal barrier (BRB). They

continue saying that DME is commonly found at any stages of DR. This is supported by another study

by (Bandello, Menchini, Merante &Truitt, 2010), which suggest that DME can influence the blood-

retina barrier.

Diabetic Retinopathy and VEGF

Diabetic Retinopathy is a common microvascular complication of diabetes mellitus – it is a

retinal microvasculopahty disease which associates with Hyperglycaemia (High blood sugar level in

the blood). DR, as defined by Behl & Kotwani (2017), is a threatening condition which is influenced

by the high blood sugar level. They suggest that the Hyperglycaemia is the key factors in the

pathological alterations (such as oxidative stress, inflammation, angiogenesis, accumulation of

advance glycation end products, overactivation of protein kinase C (PKC), increased apoptosis of

endothelial cells and neurons) target and damage the retinal blood capillaries, (p. 946). This is

supported from a study by Lo and Wang (2018), arguing that the earliest development of Diabetic

Retinopathy due to hyperglycaemia includes the dilatation of blood vessels and blood flow changes,

Pericyte loss, apoptosis of endothelial cells and the thickening of the basement membrane in the

retinal capillaries. All these earliest responses of the retinal blood vessel to hyperglycaemia

contributes to the development of DR.

It is evident from recent studies that the development of Diabetic retinopathy disease derives

from the amendments of the blood vessels in the retinal part. VEGF is a vascular endothelial growth

factor, sometimes known as vascular permeability factor. It is a type of protein generated by cells to

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

stimulates the formation of blood vessels. Studies have proved that the vascular endothelial growth

factor (VEGF) is a key factor in retinal microvasculopahty disease.

A study was taken by Falatoonzadeh, Gupta, Kenney, Kuppermann, Mansoor, Sapkal,

Sharma and Sheth (2013) supports the idea that VEGF induced angiogenesis (the formation of new

blood vessels). It is an essential factor in the development of both proliferative DR and DME, making

changes to retinal microvascular altering permeability by increasing the phosphorylation of proteins.

For example, Cheung et al. (2016) stated that:

“However, in advanced stages of DR, the high levels of VEGF and/or

erythropoieti n could favour neovascularisati on and so contribute to proliferati ve

DR90,91. Besides, erythropoieti n could potenti ate the eff ects of VEGF. Thus,

overexpression of VEGF and erythropoieti n is a double-edged sword in the

pathogenesis of DR.” (p.4)

Similarly, Marco and Veritti (2011) and Lo and Wang (2018) discovered that VEGF was increased in

the vitreous fluid of diabetic patients with proliferative diabetic Retinopathy and had significant

impacts on the Diabetic macular edema (DME).

Anti-VEGF therapy in prevention of Diabetic retinopathy.

The treatment of Diabetic Retinopathy (DR) and Diabetic macular edema (DME) has been

developed over decades. It has been confirmed by DR therapy and clinical researchers that the use

of Anti-VEGF to cure proliferative DR is more effective and safer than the standard treatments such

as Laser photocoagulation (Falatoonzadeh et al. (2013). Also, Cheung, Mitchell and Wong (2010)

support that idea arguing that “new therapies, such as intraocular injection of steroids and Anti-

VEGF, are less harmful to the retina than older therapies, and could be useful in patients who

respond poorly to conventional therapy” (p.124). They suggest that the better way to prevent

animals from getting retinal neovascularisation is by the inhabitation of the VEGF activity. This

finding supports the theory that anti-VEGF agents could cure proliferative retinopathy. Clinical trials,

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

regarding agents in Anti-therapy such as ranibizumab - the most comprehensively evaluated in

clinical trials (Lo & Wang, 2018), have been carried out and concluded that the Anti-VEGF agents

need to be injected directly into the eye to treat DR disease more efficiently. This is done to

maximize the theoretically ensuring local efficacy and to minimize as possible the systemic side-

effects (Cheung, Mitchell & Wong, 2010).

However, a study by Lo and Wang (2018) argues that there is an urgent need to develop

new treatments for proliferative DR. Though the anti-VEGF therapy is better than other standard DR

therapy and has been widely used around the world as an efficient treatment, the majority of

patients failed to achieve clinically-significant visual improvement. Limitation of anti-VEGF, as cited

in Lo and Wang (2018) are:

“The incidence of endophthalmiti s, a rare adverse eff ect of intravitreal injecti on,

may be increased by frequent injecti ons. In the DRCR.net Protocol I trial (fi ve

years), three cases (0.08%) of injecti on-related endophthalmiti s were reported

following 3973 injecti ons. Financial burden and the pati ents’ poor compliance

also limited the use of anti -VEGF drugs in clinical practi ce. Moreover, while VEGF

may play a neuroprotecti ve role in the reti na, the use of high-dose anti -VEGF

drugs requires careful considerati on.” (p. 4)

From their arguments, it obvious that anti-VEGF remains a challenging clinical treatment for DR and

thus the past research on anti-VEGF needs to be improved or recent studies should acquire more

concern on mechanism of anti-VEGF to tackle these limitations for better treatment of DR.

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

CONCLUSION

Diabetic retinopathy has been recognised as a major complication of Diabetes Mellitus,

which infected 30% of diabetic patients. Recent studies have confirmed that the Vascular endothelial

growth factor (VEGF) plays a significant role in angiogenesis and it is a leading factor for DR.

Therefore, it becomes the primary target in the DR therapy treatment. Multiple studies supported

that the vascular anti-VEGF agents, which has been approved by FDA, is the preferred choice of

treatment in case of DR and DME, as it is less destructive and safer than other standard therapy.

However, some studies disagreed. They argue that most patients failed to achieve clinically-

significant visual improvement since the anti-VEGF requires frequent injections, poor compliance of

patients and expensive. Therefore, further research on DR therapy is needed to improve the

treatment of DR. Areas to investigate further are the pathogenesis and treatment of DR.

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NAME: ADRIAN MERAKE BIOMO306 SCIENTIFIC REVIEW ARTICLE 09/09/19
ID: 1323255

REFERENCES:

Bandello, F. M., Menchini, F., Merante, D., & Truitt, K. E. (2010). Diabetic Macular Edema. Drug

Safety, 33(8), 643-652.

Behl, T., & Kotwani, A. (2017). Omega-3 fatty acids in prevention of diabetic retinopathy. Journal of

Pharmacy and Pharmacology, 69(8), 946-954.

Cheung, Larsen, M., C. M., Sharma, S., Simó, R. & Wong, T. Y. (2016). Diabetic retinopathy. Nature

Reviews Disease Primers, 2(1), 1-17.

Cheung, N., Mitchell, P., & Wong, T. Y. (2010). Diabetic retinopathy. The Lancet, 376(9735), 124-136.

Chew, E. Y. (2011). Fatty Acids and Retinopathy. New England Journal of Medicine, 364(20), 1970-

1971.

Falatoonzadeh, N., Gupta, S., Kenney, A., Kuppermann, A., Mansoor, J., Sapkal, P., Sharma, M., &

Sheth. (2013). Diabetic Retinopathy and VEGF. The Open Ophthalmology Journal, 7(1), 4-10.

Hiraoka T., Okamoto, F., Okamoto, Y., & Oshika, T. (2008). Vision-related Quality of Life and Visual

Function after Retinal Detachment Surgery. American Journal of Ophthalmology, 146(1), 85-

90.

Lo, A., & Wang, W. (2018). Diabetic Retinopathy: Pathophysiology and Treatments. International

Journal of Molecular Sciences, 19(6), 1-14.

Marco, L., & Veritti, D. (2011). Ocular Surgery News. Europe ed: Thorofare, 22(8), 30-31.