Moreover these mechanisms are also appeared to be altered by age and obesity which may possibly cause type 2 DM [ 38 ]. In past few years, environment has shown a significant role in activating diabetes, although diabetes has a trend to run in family due to intense genetic component. Obesity, older age and sluggish routine with absence of physical doings are the pronounced risk factors for getting hyperglycemia. Diabetes may cause altered epigenetic mechanisms which can direct diabetes-associated complications such as diabetic nephropathy, by altered expression of genes in target cells as depicted in Figure 2 [ 39 ].
Pathways preceding the development of microvascular complications of diabetes. Such post transcriptional alterations in target tissues resulted in specific key pathological changes in specific tissues and promote the development of specific vascular complication of diabetes.
Even after blood glucose control, synchronized crosstalk between various transcription factors and altered epigenetic mechanisms contribute to the metabolic memory and increased expression of ncRNAs that is embroiled in risk of development of microvascular complication of diabetes. High glucose can also stimulate abnormalities in DNA at key genes which are well-known to be involved in endothelial dysfunction as evident by sequencing studies in endothelial cells [ 40 ].
Tewari et al. Global DNA hypomethylation and thereby, anomalous gene expression due to hyperglycemia was observed in the animal model of diabetes, which was further correlated with inadequate wound healing process [ 43 ]. Glucose-induced insulin secretion was shown to be influenced by hyper-acetylation of H4 histone at promoter region of insulin gene [ 38 ].
Hyperglycemia has also shown to alter micro RNA miRNA , a mechanism of epigenetic modifications, which is also implicated in complications of diabetes. The alteration in miRNAa has been reported in cardiomyocyte hypertrophy in diabetes patients [ 45 ]. The elementary epigenetic modifications viz. Framework of inheritable epigenetic modifications.
DNA in chromosomes is packed round the histones to form nucleosomes. Unwrapping and accessibility of nucleosomes is regulated by alterations in histone proteins. Histone modifications include acetylation, methylation and phosphorylation. Alterations in histone tail coupled with DNA methylation and control the chromatin accessibility or inaccessibility, hence, regulating the expression of various genes.
This dynamic condition of chromatin is exposed to modifications by external stimuli via regulation of miRNAs, thus directing several pathophysiological outcomes. Methylation of DNA. It is the renowned epigenetic modification that is well studied in cancer, and lot of interest has been generated in DNA methylation in the framework of diabetes and its related complications. In detail, DNA undergoes methylation at 5th position of CpG dinucleotides and form 5-methylcytosine, which is a post-replicative mechanism.
DNA methylation is extremely dynamic process in the progress of a disease, which tends to alter related gene expressions. These alterations can be reversed by external stimuli.
Commonly repression of a gene takes place due to addition of methyl groups at promoter region on DNA, while methylation at gene bodies may regulate their transcription during elongation and also during alternative splicing [ 31 ]. Throughout the embryonic development, for de novo methylation, presence of DNMT-3a and -3b enzymes is obligatory [ 47 ].
Out of these, merely MBD2 alone is identifiable for methyl-CpG positions, which guides the interaction of methylated DNA to a multifaceted complex encompassing nucleosome remodeling and histone deacetylases HDACs bustles, thereby conducting silencing of a gene [ 48 ]. Advantage of MS-HRM is that it offers a low-cost and rapid method for the detection of even low levels of methylation at gene promoters. Diabetes-induced altered epigenetic mechanisms, resulting in modified gene expression in target cells can lead to diabetes-associated complications, such as diabetic nephropathy [ 39 ].
They also correlated the degree of methylation with time to development of DN [ 50 ]. However, studies in DN animal models or in renal cells under hyperglycemic conditions were not competent to show any significant changes in DNA methylation patterns [ 51 ].
In patients having type 2 diabetes with diabetic nephropathy, global DNA methylation variations were also observed to be associated with albuminuria in a recent study [ 52 ]. Noteworthy alterations in histone and DNA methylation patterns were observed to be present in peripheral blood mononuclear cells PBMCs of patients with membranous nephropathy [ 53 ].
Genome-wide DNA methylation study also depicted modifications in differential DNA methylation profiles among type 1 diabetes patients with or without nephropathy, where degree of methylation is linked with time towards the progression of DN [ 50 ]. It has been demonstrated that the promoter of human ACE gene, the most important and widely studied gene in pathophysiology of DN, harbor CpG islands.
ACE transcription and expression levels were also observed to be influenced by methylation in its promoter region both in vivo and in vitro [ 54 ].
The magnitude of epigenetic alterations, particularly DNA methylation, has been shown to correlate with ACE activity levels [ 54 , 55 ]. Global DNA methylation variations were also observed to be associated with albuminuria in a recent study [ 52 ]. Additionally alterations in DNA methylation of ACE promoter are suggested to be a fundamental cause of major depression MD and a shared pathogenic factor for bi-directional connection between MD and cardiovascular disorders [ 56 ].
Apart from the importance of DNA methylation in DN, their role in DR is not clear, however, DNA methylation has been shown to control the expressions of many genes associated with retinal homeostasis. Previous studies have shown the link of DR development and DNA methylation, which indicates that DR may be associated with epigenetic alterations.
They assumed that PBMCs could be used as a predictor for diabetic retinopathy. Another study evaluated global DNA methylation levels in blood leukocytes in persons with and without retinopathy [ 58 ]. They found a significantly higher global methylation levels in patients with DR than those without DR. However, it does not benefit DNA methylation machinery by the reversal of hyper-glycemic environment for shorter duration [ 59 ].
In people with diabetes mellitus, it has been seen that activity of Dnmt1 enzyme was elevated in retinal and its capillary cells. However, this was not observed with Dnmt-3a or Dnmt-3b [ 60 , 61 ]. Histone modifications:. It is the interesting and emerging mechanism that exhibits the addition of methyl groups at histones related to a gene. As DNA is structured into chromosomes in eukaryotic cells, it is tightly wrapped onto series of nucleosomes the basic unit of chromatin , which are the octamer complexes of small core a H3-H4 tetramer and two H2A-H2B dimers linked by linker histone proteins H1 [ 62 ].
These histones are involved in post-translational modifications PTMs which may regulate gene expressions. The gene activation and repression are determined by dynamic chromatin structure that directly depends upon these PTMs, as they will allow transformation of inactive or repressive chromatin to euchromatin, the active condition of chromatin.
These modifications, like DNA methylation, are able to regulate the gene expression without any change in its DNA sequence. Hence, histone tails can be acetylated, methylated, or phosphorylated. Histones with methylated Kme or acetylated Kac lysine residues, mostly at amino terminal tails, have been identified.
Generally, these modifications are correlated with either gene activation or repression. Like, on one hand, histone lysine acetylation H3K9ac, H3K14ac and H4K5ac is generally associated with gene activation that opens the chromatin for the binding of transcription machinery [ 63 ]. Histone acetylation is tightly controlled by the equilibrium between acetylation HATs and deacetylation HDACs enzymes that add or deletes acetyl group.
On the other hand, methylation on lysine or arginine residues can be correlated with both, gene activation or gene repression, depending on the residue to be modified. Although, mono-methylation of histone 3 at lysine residue 9 H3K9me mediated by suppressor of variegation 3—9 homolog 1 SUV39H1 is correlated with gene activation whilst, its trimethylation H3K9me3 is linked with gene repression [ 65 ].
Additionally, H3K27me3 and H4K20 were associated with gene repression. Afterwards, lysine demethylases LSD1 are there to reverse such steady modifications at H3K4 and H3K9 [ 66 , 67 ] as a co-repressor or co-activator respectively. In a study in lymphocytes from type 1 diabetic patients, as compared to controls increased H3K9me2 levels were reported to be correlated with immune and inflammatory pathways associated with diabetes and its complications including DN [ 69 ]. Such histone modifications at N-terminal are two key mechanisms that may alter development and progression of diabetes and its related complications; they are noteworthy as discussed below.
In DN pathogenesis, expressions of a gene that are associated with DN are regulated by post-translational modifications of histone proteins, apart from DNA methylation. Alterations in DNA methylation and H3K9Ac at gene promoters were found to be associated with endothelial dysfunction in endothelial cells cultured in hyperglycemic conditions.
Among various epigenetic mechanisms, methylation among core histone tails is considered to be the highly stable PTM that could be a key factor in the pathogenesis of various complications of diabetes. In glomeruli of diabetic mice, increased chromatin active marks along with decreased repressive marks were observed at PAI-1 and receptor for AGE RAGE gene promoters as compared to control, which showed the regulation of histone modifications in kidney in the presence of hyperglycemia [ 72 ].
In the animal models of DN, increased histone active marks H3K4me2 and decreased repressive marks H3K27me3 were observed to be associated with the expression of genes related to DN [ 73 ]. Histone post-translational modifications have also been studied extensively in the context of DR.
Increased oxidative stress and simultaneous decreased levels of retinal superoxide dismutase SOD2 are the key features of DR. Acetylation of core histone protein on lysine residues is thought to opens up the DNA, thereby, increased availability for binding of transcription factors. These coactivator molecules then, regulate the expressions of target gene owing to their HAT activity [ 77 ].
Contrary to this, recruitment of HDACs results in compact chromatin, coiled DNA and less accessibility for binding of transcription factors to DNA, thereby decreased expression of target gene. Hence, the balance between acetylation and deacetylation of histones regulates the transcription of the gene. Increased HDACs and decreased HATs along with decreased global histone acetylation activities were also found in diabetic retinal cells in the models of diabetic retinopathy [ 78 ].
However, reversal of hyperglycemic conditions did not able to restore changes in histone activities. This is in contrast to a study in diabetes where activation of histone acetylation was observed in retinal cells [ 79 ].
These guidelines are based on findings from lipid-lowering trials that included diabetic patients and were confirmed by subsequent trials. Post-hoc analyses of diabetic patients who were included in lipid-lowering trials have supported the notion that these patients have comparable relative reductions or perhaps greater absolute reductions in the risk for CVD events than their nondiabetic counterparts.
These data are summarized in the ACP guidelines. These guidelines are still recommended by the AACE. In patients with diabetes, large clinical trials have demonstrated favorable effects of BP control on reducing CVD risks. The beneficial effects could not be entirely attributed to BP reduction in these trials. Intervention trials have shown a somewhat modest relationship between glycemic control and CVD risk. A patient with diabetes should be referred to an endocrinologist if targets for glycemic control cannot be achieved or if the patient is experiencing severe hypoglycemia.
It is important to refer patients early in the disease stage to help them avoid long-term complications. Also, patients who develop complications should be referred to an endocrinologist to see if glycemic control can be improved or simply to treat the complications.
Aspirin should be used in combination with clopidogrel for up to 1 year in these patients following acute coronary syndrome. The watchword of the ADA is that diabetes is a serious disease associated with significant morbidity and mortality related to microvascular and macrovascular complications. Careful screening for these complications provides clinicians with opportunities to reduce the risk for their development and progression.
Aggressive interventions with glycemic control, as well as management of lipids and blood pressure, seem to have favorable effects on many complications of diabetes. Aspirin therapy has been shown to reduce the CVD risk in these patients. These screening and intervention strategies are supported by robust observational and intervention trial data and, in turn, are endorsed by the various organizations that have written disease management guidelines.
Zimmerman, MD. Zimmerman Published: September Definitions Microvascular complications of diabetes are those long-term complications that affect small blood vessels. Retinopathy is divided into two main categories: Nonproliferative retinopathy and proliferative retinopathy. Nonproliferative retinopathy is the development of microaneurysms, venous loops, retinal hemorrhages, hard exudates, and soft exudates. Proliferative retinopathy is the presence of new blood vessels, with or without vitreous hemorrhage.
It is a progression of nonproliferative retinopathy. Diabetic nephropathy is defined as persistent proteinuria. It can progress to overt nephropathy , which is characterized by progressive decline in renal function resulting in end-stage renal disease.
Neuropathy is a heterogeneous condition associated with nerve pathology. The condition is classified according to the nerves affected and includes focal, diffuse, sensory, motor, and autonomic neuropathy. Table 1. Screening for micro- and macrovascular complications in patients with diabetes. Complication Detection Microvascular Retinopathy Dilated eye examination fundus photography Intravenous fluorescein angiography Optical coherence imaging Nephropathy Urine micoalbumin Neuropathy Monofilament testing Macrovascular Hypertension Measure blood pressure, every visit Dyslipidemia Fasting lipid profiles, at least annually.
Figure 1: Click to Enlarge. Table 2. Goals of medical-nutrition therapy for patients with diabetes. Achieve optimal metabolic outcomes by attaining and maintaining the following: Blood glucose levels in the normal range or as close to normal as is safely possible Lipid and lipoprotein profiles that reduce risk for macrovascular disease Blood pressure levels that reduce risk for vascular disease Modify nutrient intake and lifestyle as appropriate to prevent and treat obesity, dyslipidemia, CVD, hypertension, and nephropathy Improve health through healthy food choices and physical activity.
Specific patient populations Children and adolescents with type 1 DM Provide adequate energy to ensure normal growth and development. Integrate insulin regimens into usual eating and physical activity habits. Children and adolescents with type 2 DM Facilitate changes in eating and physical activity habits that reduce insulin resistance and improve metabolic status. Pregnant and lactating women Provide adequate energy and nutrients needed for optimal outcomes. Older adults Provide for the nutritional and psychosocial needs of aging adults.
Patients treated with insulin or insulin secretagogues Provide self-management education for treatment and prevention of hypoglycemia, acute illnesses, and exercise-related blood glucose problems. Population at risk for diabetes Decrease risk by encouraging physical activity and promoting food choices that facilitate moderate weight loss or at least prevent weight gain.
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Diagnosis and management of diabetic neuropathy. Clin Geriatr Med ; — Circulation ; — Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial.
JAMA ; — Jindal V. Neurodegeneration as a primary change and role of neuroprotection in diabetic retinopathy. Mol Neurobiol ; National Kidney Foundation.
Nutrition recommendations and interventions for diabetes— a position statement of the American Diabetes Association. Dietary carbohydrate amount and type in the prevention and management of diabetes: a statement by the American Diabetes Association.
International table of glycemic index and glycemic load values: Am J Clin Nutr ; Reply to R Mendoza. Glycemic load values [Letters to the Editor]. Am J Clin Nutr ; — Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med ; — Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
Diabetes Res Clin Pract ; — Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS Lancet ; — Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS BMJ ; — Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes.
Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet ; 1 — Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data.
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Circulation ; 25 Suppl 2 :S1-S The time to develop microvascular complications is much faster and common than macrovascular complication [ 3 ]. Diabetes mellitus DM , commonest metabolic illness, is one of the major public health concern worldwide [ 4 ].
Diabetes burden has been rising more rapidly in low and middle income countries than in high income countries [ 3 , 5 ], which is attributed to the effect of globalization, life style modification change in diet type and pattern and physical inactivity being obese [ 6 ].
Nowadays, the number of peoples living with diabetes increases rapidly and the disease become pandemic. Since few decades, the prevalence of type 2 diabetes has increase radically in all countries of the globe.
It is about million people have diabetes mellitus worldwide, and low-and middle-income countries are majorly the victims [ 5 ]. The disorder is also predicted to million in and inflated to million by the year [ 7 ].
Morbidity and mortality in chronic diabetes mellitus is now common that is more than four million people aged 20—79 years were estimated to die from diabetes related complications [ 7 ]. Adequate data on tendencies of microvascular diabetes complications and other evolving complications are lacking and so that conclusions are incomplete [ 8 ].
Following the increase number of type 2 DM, its microvascular complication is rising proportionally and substantially [ 9 ]. Diabetic microvasculature is highly susceptible for damage due to chronic hyperglycemia and genetic predisposition, leading to complications of essential organs such as the kidneys, the eyes and the nervous system.
Diabetic nephropathy is the foremost cause of serious renal disease, diabetic retinopathy DR is the amongst cause of blindness in diabetes population and that of diabetic neuropathy is the main attributing factor for diabetic foot ulcer and amputation [ 9 , 10 ]. Almost all organs are affected and people suffer from serious morbidity and mortality due to type 2 DM related complications. The commonest type 2 DM microvascular complications are retinopathy, neuropathy and nephropathy that are present at the time of patient diagnosis [ 4 , 11 ].
Chronic diabetes prone to lose more than half of the direct health costs following complications [ 12 ]. Indeed, they are eligible to develop disability, accelerate mortality and fail to avail work on regular basis due to the illness [ 1 , 8 , 13 ].
The emerging prevalence of diabetes and its complication also noted in Ethiopia. For instance, microvascular complication of type 2 diabetes is prevalent in Gondar, Ethiopia Different literature showed that a number of factors are associated with microvascular diabetic complications. These factors could be grouped as socio-demographic factors age, sex, and marital status , behavioral factors obesity, diet and clinical factors glycemic control, and duration of diabetes, comorbidities hypertension and medication.
In particular studies, being female [ 28 , 31 ], age [ 14 , 16 , 19 , 22 , 26 , 30 , 32 , 33 ], marital status single or divorced [ 19 , 27 ], family history of diabetes mellitus [ 15 , 26 , 28 , 31 ], longer duration of diabetic [ 9 , 16 , 19 , 22 , 23 , 26 , 27 , 30 , 31 , 32 , 34 ], hypertension [ 9 , 16 , 18 , 19 , 20 , 22 , 23 , 26 , 27 , 30 , 32 , 34 , 35 ], obesity [ 22 , 27 , 31 ], poor glycemic control [ 18 , 22 , 25 , 27 , 28 , 33 , 34 ], adherence to diet [ 16 , 22 , 35 ], mixed medication [ 26 , 30 ] and insulin therapy only [ 22 ] were predictors for microvascular complications among type 2 diabetes mellitus patients.
Literature sources that showed factors exacerbating diabetic complications were too limited. Hence, this study was aimed to assess prevalence of microvascular complications and its predictors among type 2 diabetes mellitus patients in Dessie town hospitals.
Around fourteen thousand diabetes patients were served in a total of 5 hospitals. Diabetes patients have follow-up dates from Monday to Friday. Type 2 diabetes clients visiting the Hospitals at a regular base every 3 months as outpatient and available during the period of data collection were participants and eligible for this study. Those individuals living with diabetes who were critically ill or unconscious, gravid women at 2nd trimester and above were excluded.
We used simple random sampling technique to recruit study participants and allocated proportionally for each hospital of Dessie town. Independent variable: Socio-demographic factors age, sex, residence, marital status, occupation , behavioral factors physical activity, obesity, diet and clinical factors glycemic control, and duration of diabetes mellitus, comorbidities hypertension and anti-diabetic medication. Microvascular complications: Diabetes mellitus patients with one or more of the following complications: diabetic nephropathy, diabetic retinopathy, and peripheral neuropathy [ 14 ] of known diabetes or newly diagnosed diabetes.
Physical activity: Diabetes mellitus individuals who perform at least min per week 3 days of moderate intensity exercise regarded as Good otherwise poor physical activity [ 37 ].
It has three categories, category 1 BMI: 30— Adherence to diet: Diabetes mellitus individuals adjust life style diet as recommended for more than 3 days in last seven consecutive days. These complications were diagnosed based on the physical, clinical, laboratorial and other requested findings and decision by the physician. Fundus ophthalmoscopy examination the presence of neovascularization, hemorrhage spot, vitreous hemorrhage, microaneurysm, macular lesion and cotton wool spot was done to diagnose diabetic retinopathy.
For neuropathy, clinical assessment like history of numbness, paresthesia, tingling sensation and tests for vibration sensation was used. Likewise, symptoms such as swelling of feet, hands or eyes, urinary frequency and urgency, BP measurement and tests like protein in the urine, renal function tests and ultrasound were used diabetic nephropathy. Participants were interviewed and their medical chart was reviewed by trained data collectors to determine clinical and related factors.
Data quality was assured by giving training prior to data collection and data collectors were supervised and applied measurements at least twice and the average was taken with the nearest value of 0.
Routinely, diabetes patients who had follow-up in diabetic clinic of each hospital were ordered to come to the next visit with their FBS result and data collectors used the newly FBS result. The data collection tools and instruments used were developed by for this study after reviewing different related literatures.
The tool was modified based on the observed findings from the pre-test result. Some questions having ambiguous meaning were rewritten for better understanding of study participants. Data were cleaned, coded and entered into Epi-Data 3. Frequency tables with percentage, median, and interquartile range IQR was used to describe study findings. Model fitness was verified by Hosmer and Lemeshow model fit and variance inflation factor tested variables multicollinearity.
A total of type 2 diabetes mellitus were took part in the study. The median age of participants was 53 years IQR: 45—60 years. More than half of the clients [ Majority of individuals [ Quarter of [78 In this study, the prevalence of at least one microvascular diabetic complications was Specifically, the prevalence of retinopathy, In this study, majority of individuals [ The drugs of choice for Two hundred and eight Majority of them, [ Only quarter [66 In the final model, age of participants, duration of diabetes and co-morbid hypertension were statistically significant with the occurrence of microvascular complications.
The odds of developing at least one diabetes microvascular complications for age groups 60—87 yeas was 2. Moreover, diabetic clients with co-morbid hypertension were 3. Nowadays, diabetes mellitus is alarmingly increasing chronic disease that has short and long term sequels if early medication and life-time modification is not sought. Likewise, the disorder is growing faster and becoming serious medical problem in Ethiopia. Microvascular complications could lead to visual, renal and neurological malfunction that all together results in sever morbidity, mortality and negative socio-economic consequences.
Hence, identifying associated factors of microvascular complications is very crucial to halt its irreversible consequences.
In the current study, the overall prevalence of microvascular diabetic complications was This proportion is in line with studies in Jimma, Ethiopia However, this finding is higher than studies in Gondar Ethiopia On the other hand, this result is lower than studies in Debre Tabor, Ethiopia The current study concludes retinopathy In this study factors like increasing age of participants, duration of diabetes and co-morbid hypertension were significantly associated with the presence of microvascular complications.
This is probably due to with advanced age, there combined effect of insulin resistance and loss of beta cells that brings hyperglycemia which in turn causes microvascular damage. Moreover, being older is a powerful predictor of vascular damages. They also develop premature complications and death as compared to younger age [ 41 ]. Participants who had a duration of diabetes more than 5 years was 4 times more likely to have microvascular complications in contrary to duration of diabetes 5 years or less.
Longer diabetic duration was a potential risk factor for both microvascular diseases and macro-vascular disease independently [ 16 , 18 , 42 ]. In parallel to diabetes longer duration, there is chronic asymptomatic hyperglycemia that ends up with susceptible organ damage at diagnosis [ 36 ]. Diabetes clients with co-morbid hypertension were 3. The possible justification is that high blood pressure accelerates the progress and development of microvascular complications due to increased intracellular hyperglycemia through up regulation of the glucose transporter 1 [ 43 ] so that increased plasma glucose level leads to damage of retinal blood vessels and glomeruli, also impair regulation of retinal perfusion [ 17 ].
Indeed, hypertension had direct effect on retinal endothelial cell and function that causes cell growth and vasoconstriction which eventually predisposes patients to vascular complications [ 21 , 44 ]. Unlike to this study, factors such as treatment regimen, poor physical activity and adherence to diet are significant for microvascular complication at Debre Tabor [ 30 ], Kuwait [ 22 ], Greenland [ 12 ], Bangladesh [ 21 ], and China [ 19 ]. Also this study was an institution-based so that it is unable to generalize the findings to the entire populations.
Recall bias is an expected additional limitation. The current study findings revealed that microvascular complications of diabetes were widespread particularly diabetic retinopathy that needs immediate intervention to halt its undesirable outcome of vision loss.
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