Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
DIABETIC RETINOPATHY (LITERATURE REVIEW)
Yuldasheva M. Nodirakhon MD
RSSPMC Endocrinology named after
Acad.Y.KH.Turakulov,
The head of the Department of
Retinal and Optic Nerve Pathology,
Doctor of Medical Sciences.
Fazliddinova Sh. Mekhribonu MD
Tashkent Pediatric Medical Institute
Annotation
. The article provides a review of the literature on the topic of diabetic
retinopathy. In this regard, reliable literature is used and current information is highlighted.
Key words:
diabetic retinopathy, type 2 diabetes mellitus, dynamics, symptoms.
Abstract
. Retinal damage is one of the specific complications of diabetes mellitus, which is
the main cause of blindness in this category of patients. Currently, there are 5 million blind
people and 180 million with low vision in the world. Presumably, by 2030, the number of
blind people will increase by 27%, and people with low vision by 45% (WHO, 2002).
Diabetic retinopathy (DR) was first described more than 100 years ago by Mac Kenzi in
1879, however, today this complication of diabetes mellitus is a major problem for health
care.
Despite the widespread introduction of new effective drugs and instrumental methods for
diagnosis and treatment, DR still remains the main cause of vision loss. Different figures are
given for the prevalence of DR in type 1 and type 2 diabetes in different countries. In
patients with undiagnosed type 2 diabetes, signs of DR are detected at the time of diagnosis
in 7-30% of patients. Moreover, proliferative DR is not a big problem for them, in contrast
to type 1 diabetes, while diabetic maculopathy becomes the main cause of visual acuity
deterioration. Among the factors causing DR progression are the degree of compensation of
carbohydrate metabolism, duration of diabetes, age, arterial hypertension, nephropathy,
pregnancy, and smoking. DR is characterized by the presence of specific vascular anomalies
andRetinal damage is one of the specific complications of diabetes mellitus, which is the
main cause of blindness in this category of patients. Currently, there are 5 million blind
people and 180 million with reduced vision in the world. Presumably, by 2030, the number
of blind people will increase by 27%, and people with reduced vision by 45% (WHO,
2002). Diabetic retinopathy (DR) was first described over 100 years ago by Mac Kenzi in
1879, however, this complication of diabetes mellitus still represents a major health problem
today. Despite the widespread introduction of new effective drugs and instrumental methods
for diagnosis and treatment, DR remains the main cause of vision loss. Different figures are
Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
given for the prevalence of DR in diabetes mellitus types 1 and 2 in different countries. In
patients with undiagnosed DM 2, signs of DR are detected at the time of diagnosis of the
disease in 7-30% of patients. Moreover, proliferative DR is not a big problem for them, in
contrast to DM 1, while diabetic maculopathy becomes the main cause of visual acuity
deterioration. Among the factors causing DR progression, the degree of compensation of
carbohydrate metabolism, duration of diabetes, age, arterial hypertension, nephropathy,
pregnancy, and smoking are distinguished. DR is characterized by the presence of specific
anomalies of the vessels and tissues of the retina. It is characterized by a change in the
caliber and tortuosity of the retinal vessels, the appearance of microaneurysms, hemorrhages,
edema, hard and soft exudates, newly formed vessels, glial proliferation, and vitreoretinal
traction. The study of the morphological picture of DR revealed thickening of the basement
membrane, loss of capillary pericytes, and as a result, the development of capillary
acellularity, which leads to the fact that the microcapillaries are represented by tubes
consisting of the basement membrane. Oxygen perfusion through the wall of the latter
deteriorates and retinal ischemia and hypoxia develop. All this leads to the development of
neovascularization, the newly formed vessels, in turn, are functionally defective and become
a new source of hemorrhages. According to the authors, the retina may be especially
sensitive to damage, since it has the highest rate of glucose and oxygen utilization per unit
weight than any other tissue, and has a high activity of the glycolytic and anaerobic
pathological pathway of glucose metabolism.
It is an undeniable fact that chronic hyperglycemia plays the main role in the development of
DR. There are data obtained as a result of multicenter studies performed in diabetes mellitus,
confirming the primary importance of normoglycemia. Maintaining the state of
normoglycemia in patients with type 1 diabetes confirmed a significant reduction in the risk
of progression of microvascular complications.
The results of the international study – Diabetes Control and Complication Trial showed that
maintaining satisfactory glycemic control in a group of people without vascular
complications contributed to a decrease in the risk of developing: diabetic retinopathy – by
76%, diabetic neuropathy – by 60%, microalbuminuria – by 30%, albuminuria – by 54%. A
multicenter study conducted in patients with type 2 diabetes in the UK and its results were
presented in 1998. Normoglycemia reduces the risk of complications of diabetes by 12%,
myocardial infarction by 16%, microvascular complications by 25%. BP control reduces all
complications by 24%, strokes by 44%, heart failure by 56%, microvascular complications
by 37%, mortality by 32%.
The age of patients with type 1 diabetes can be considered as a risk factor. It is well known
that DR is extremely rare in childhood. However, with the onset of puberty, microvascular
complications, including diabetic retinopathy, rapidly progress. This is due to the fact that
during this period, there is a powerful hormonal restructuring, accompanied by the
production of a large number of counter-insular factors - pituitary tropic hormones, sex
steroids, growth factors. The decompensation of diabetes that develops during this period
can be explained by a rapid increase in div weight and, as a result, an increase in the need
for insulin. The puberty period is the most threatening in terms of DR progression. The
participation of hypertension as a major risk factor in the development and progression of
DR has been proven. The results of the Wiscongin Epidemiological Study of Diabetic
Retinopathy (WESDR) showed that an increase in diastolic pressure by every 10 mm
Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
Hg. increases the risk of progression of proliferative DR by 50%. There is data on the
relationship between systemic hypertension and the frequency of development of exudates,
hemorrhages, and other severe retinal damage. The presence of dyslipidemia also adversely
affects the course of DR. Clinical data on a close relationship between the level of
cholesterol and the presence of hard exudates in the retina have been published. Thus, an
increase in the cholesterol level by 50 mg% in elderly patients with type 1 diabetes caused
an increase in the frequency of hard exudates in the retina by 50% (WESDR). In these
groups of ETDRS (barby Treatment of Diabetic Retinopathy Study), a close relationship
was shown between elevated levels of cholesterol, low-density lipoproteins (LDL) and
triacylglycerides (TG) with the frequency of detection of hard exudates in the retina.
The relationship between smoking and retinopathy progression is unclear. Smoking
probably causes hypoxia and cerebral vasospasm, which affects DR progression. The
WESDR study (1998) found a relationship between different HLA antigens and DR, a
relationship with glycated hemoglobin levels, hypertension, diabetes duration, and
increasing proteinuria. Proliferative retinopathy was found to develop 5.4 times more
frequently compared to the group without HLA haplotypes DR3 and DR4. At the same time,
observation of a cohort of patients with HLA DR4 did not reveal any progression of DR
compared to the group without these antigens. This process is probably controlled to a
greater extent by other risk factors. The biochemical processes that lead to morphological
changes in the retina have been studied quite well. The trigger is chronic hyperglycemia,
which leads to activation of aldose reductase activity, increased non-enzymatic glycation of
proteins, changes in myo-inositol phosphatidimenositol mechanism, increased activity of
protein kinase C, decreased heparin sulfate proteoglycan, increased glucose autoxidation,
changes in the activity and levels of vasoactive substances such as endothelin, prostanoids,
nitric oxide, histamine, etc. One of the mechanisms of the pathological process may be
thickening of the capillary basement membrane, which in turn, hypothetically leads to
closure of the retinal capillaries. However, this hypothesis was not confirmed, since the use
of aldose reductase inhibitors in patients with type 1 diabetes did not prevent the progression
of DR with their help.
The relationship between non-enzymatic and/or enzymatic glycation of proteins and the
progression of diabetic retinopathy has been proven. According to the authors, diabetic
retinopathy develops as a consequence of retinal ischemia. Vascular damage, consisting of
thickening of the basement membrane, loss of pericytes, focal proliferation of endothelial
cells, obliteration of capillaries, the appearance of microvascular shunts - this entire complex
of lesions is diagnosed as diabetic microangiopathy. In addition to damage to the vessel wall,
there is a change in blood viscosity and properties of formed elements of the blood.
Hyperglycemia, which is a consequence of insulin deficiency, causes an increase in the
release of growth hormone. An increase in the level of growth hormone in conditions of
hypoinsulinemia changes the synthesis of proteins by hepatocytes, which leads to
dysproteinemia;
increased fibrinogen and α2-globulin levels enhance erythrocyte
aggregation, hyperglycemia worsens prostocyclin production by endothelial cells; increased
erythrocyte and platelet aggregation causes hemodynamic disturbances in the
microcirculation system; impaired blood flow in the microcirculation system leads to
hypoxia and retinal ischemia; hypoxia and retinal ischemia cause excessive production of
vasoproliferative growth factor, which stimulates the growth of new vessels around the optic
nerve head and in other areas of the retina. Vasoproliferative factors are peptides with
Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
pronounced mitogenic properties. Similar properties are attributed to fibroblast growth
factors - FGF, vascular endothelial factor - VEGF, insulin-like growth factor - IGF and
others.
Thus, chronic hyperglycemia, being the initiating factor in the development of diabetic
retinopathy, causes a number of biochemical disorders. This is followed by functional
changes in the retina: slowing of blood flow and oxygen saturation, disruption of retinal
electrophysiology, increased capillary permeability.
All this leads to morphological changes in the retinal vessels: loss of pericytes, thickening of
the basement membrane, development of capillary acellularity, desolation of capillaries,
formation of microaneurysms and hemorrhages, proliferation of the endothelium,
neovascularization.
Classification of diabetic retinopathy
Currently, most countries use the classification proposed by Kohner E. et al. There are three
stages: Stage I – non-proliferative DR (there are microaneurysms, hemorrhages, edema,
exudates; the indicated pathophysiological changes are not sharply expressed and are
isolated); Stage II – preproliferative DR (characterized by the presence of venous anomalies,
a large amount of exudates, multiple large retinal hemorrhages); Stage III – proliferative DR
(there are massive hemorrhages in the retina, vitreous div, neovascularization of the optic
nerve head and/or peripheral areas of the retina, fibrous tissue in the area of preretinal
hemorrhages, vitreoretinal tractions and retinal detachment). Newly formed vessels of the
iris (rubeosis) are often the cause of secondary glaucoma. It should be noted that in the early
stages of diabetic retinopathy, there are no changes in visual acuity, and therefore patients do
not seek help. In this regard, the importance of screening for diabetic retinopathy increases.
Treatment of diabetic retinopathy consists primarily in reducing risk factors and includes
control of hyperglycemia, hypertension, hyperlipidemia, detection and treatment of retinal
damage itself. At present, the issue of the need to maintain a high degree of compensation of
carbohydrate metabolism in all patients with diabetes has been clearly resolved. The
appearance of fresh hemorrhages in the retina after hypoglycemia has been established. For
this reason, it is necessary to select adequate hypoglycemic therapy, gradually achieving a
decrease in glycated hemoglobin (HbA1c) by about 1% per month.
A number of drugs were used for drug treatment of DR: anabolic steroids, drugs that prevent
platelet aggregation (aspirin, dipyridamole, ticlopidine), aldose reductase inhibitors,
clofibrate, pravastatin, aminoguanidine, ACE inhibitors, hormonal antagonists of growth
hormone (octreotide, somatostatin), protein kinase C inhibitors. The latter drugs reduce the
production of various growth factors that play a decisive role in the development of
neovascularization. A promising direction in conducting research on the effective treatment
and prevention of diabetic retinopathy, especially in the early stages of its development, are
herbal preparations, the advantage of which is determined by low toxicity, "softness" and a
wide range of pharmacological effects. Complex herbal therapy as a means of additional
treatment in combination with synthetic drugs can find application in the initial stages of the
disease, at the stage of anti-relapse and rehabilitation therapy.
Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
Conclusion
It is necessary to conduct the first examination by an ophthalmologist 1.5-2 years after the
onset of the disease in patients with type 1 diabetes and together with the diagnosis in
patients with type 2 diabetes. In childhood, the first examinations should begin at the age of
10 (from the beginning of puberty).
If the disease is progressing favorably, these examinations should be repeated once a year, if
pathology is detected - once every 3-6 months. In the presence of additional risk factors
(pregnancy, nephropathy, arterial hypertension), the question of the frequency of
examinations is decided individually. If complaints of a sudden decrease in visual acuity
appear, it is necessary to urgently refer the patient to an ophthalmologist.
Thus, a promising direction in the treatment of diabetic retinopathy remains the education of
patients and doctors, achieving the highest possible level of glucose and blood pressure
control throughout the life of a patient with diabetes, providing patients with the most
modern hypoglycemic drugs, including herbal preparations, self-monitoring tools,
mandatory and timely screening and monitoring of patients, and the development of new
effective drugs and treatment methods.
References
1. BrennerB. et al. Renaal Study Investigators: effects of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes and nephropathy // N. Engl. J. Med.
– 2001. –Vol. 345. – P. 861–869.
2. Castello I.B. Hyperlipidemia: a risk factor for chronic allograft dysfunction // Kidney mt.
–2002.–Vol. 61 (suppl. 80). – P. 1923–1928.
3. Coresh J., ActorB.C., GreenT. Etal. Prevalence chronic kidney disease and decreased
kidney function in the abult US population: third national health and nutrilion examination
survey // Am. J. Kidney Dis. – 2003. – N 41. – Р. 1–12.
4. Decochez K., Truyen I., AuweraB.V. et al. (Belgian diabetes Relgian) Combined
positivity for HLA DQ2( DQ8 and 1A-2 antibodies defines population and high risk of
developing type 1 diabetes // Diabetologia. – 2005. – Vol. 48, N 4. – Р. 687–690.
5. Forhan J.M., Balkan B. et al. Is microalbuminuria an integrated risk marker for
cardiovascular disease and insulin anct in both men and women? // J. Cardiovasc. risk. –
2001. – Vol. 8. – P. 1007–1009.
6. Go A.S., Chertov G.M., Fan D. et al. Chronic kidney disease and the risks of death,
cardiovascular events, and hospitalization // N. Engl. J. Med. – 2004. – Vol. 351 (suppl 13).
– P. 1296–1304.
7. Halteren A.G.S., Kardol M.J., Mulder A. Homing of human autoreactive T-cells into
pancreatic tissue of NOD-SCID mice // Diabetologia. – 2005. – Vol. 48, Suppl. 1. – P. 75–
82.
Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
8. Han D., Hamilton R.T., Lam P.J. et al. Lipoic acid: energy production antioxidant activity
and health effects. – N.Y.: CRC Press, 2008. – Р. 293–315.
9. Januzewsky A.S., Alderson N.L., Metz T.O.et al. Role of Lipides in chemical
modification of proteins and development of complications in diabetes // Biochem. Soc.
Trans. – 2003. – Vol. 31, N 6. – Р. 1413–1416.
10. Sjoilie A.K., Klein R., Porta M. et al. Direct Programme Study Group, Effect of
Candesartan on progressin and regression retinopathy in type 2 diabetes (DIRECT-Protect2);
a randomised placebocontrolled trial // Lancet. – 2008. – Vol. 372. – P. 1385–1393.
11. Verma S., Fedak P.W.M., Eeisel R.D. Fundamentals of reperfusion injury for the clinical
cardiologist // Circulation. – 2002. – Vol. 105. – P. 2332–2336.
12. Yamasaki M., Kawabe A., Nishimoto t al. Dihidroalpha-lipoic acid has more patent
cytotoxicity than alpha-lipoic acid // In Vitro Cell. Dev. Biol. Amm. – 2009. – Vol. 45, N 5–
6. – P. 275–280.
