Review Article: Journal of Drug and Alcohol Research (2025) Volume 14, Issue 12

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Navigating the Landscape of Diabetic Microvascular Complications: Strategies for Prevention and Management

Anastasia V. Poznyak1*, Elizaveta Romanovna Korchagina22, Olesya Olegovna Galanova3, Sergey Alekseevich Protasov4 and Alexander N. Orekhov1
 
1Institute for Atherosclerosis Research, Osennyaya 4-1-207, 121609 Moscow, Russia
2Department of Systemic Rheumatic Diseases, Nasonova Research Institute of Rheumatology, 34A, Kashirskoe Shosse, 115522 Moscow, Russia
3Moscow Center for Advanced Studies, 20, Kulakova Street, 123592 Moscow, Russia
4Talrose Institute for Energy Problems of Chemical Physics, Semenov Federal Research Center for Chemi, 38-2, Leninsky Prospekt, 119334 Moscow, Russia
 
*Corresponding Author:
 Anastasia V. Poznyak, Institute for Atherosclerosis Research, Osennyaya 4-1-207, 121609 Moscow, Russia, Email: tehhy_85@mail.ru

Received: 06-Nov-2025, Manuscript No. JDAR-25-173180; Editor assigned: 07-Nov-2025, Pre QC No. JDAR-25-173180 (PQ); Reviewed: 21-Nov-2025, QC No. JDAR-25-173180; Revised: 28-Nov-2025, Manuscript No. JDAR-25-173180 (R); Published: 05-Dec-2025, DOI: 10.4303/JDAR/236484

Abstract

As the global prevalence of Diabetes Mellitus (DM) continues to rise, projected to affect nearly 700 million individuals by 2045, the burden of associated macro-and Micro-Vascular Complications (MVCs) is escalating markedly. This review synthesizes current knowledge regarding the development, risk factors, prognostic implications, and preventive strategies for key diabetic MVCs, including Diabetic Retinopathy (DR), nephropathy, peripheral neuropathy, and autonomic neuropathy. Evidence underscores a significant link between these complications and cardiovascular risk, revealing that MVCs often predict cardiovascular events with greater accuracy than traditional risk factors such as hypertension and glycemic control. Through a comprehensive exploration of epidemiological findings, clinical trials, and treatment strategies, this review highlights the importance of early detection and rigorous management of diabetic MVCs. Key interventions, including angiotensin-converting enzyme inhibitors, statins, and effective glycemic control, are discussed as vital measures to mitigate the progression of diabetic complications. Additionally, we emphasize the necessity for routine screening, particularly for high-risk populations, to enable timely intervention and improve patient outcomes. By integrating clinical guidelines with advancements in diabetes care, our findings propose a multifaceted approach to reducing the burden of diabetic microvascular diseases.

Keywords

Diabetes mellitus; Retinopathy; Nephropathy; Glycemic control

Introduction

Evidence from the year 2019 indicate that the number of individuals suffering from DM was 463 million, which is prognoses to be up to seven hundred million by 2045. Raising rates of the disease and elevation of time periods spent with DM affected the progression of macro-and micro-vascular complications considerably. Healthcare systems hereby are experiencing an enormous burden worldwide [1,2]. Whereas decrease in CV complications, CV deaths and limb amputation frequency were observed in the past twenty years, especially in developed countries, the worldwide burden of CVD, DR, and renal failure in patients with DM has elevated drastically [3,4]. The Discover trial demonstrated that the highest rates of MVCs in subjects with T2DM were found in Europe, and the lowest in Africa, 23.5% and 14.5% of the total 18.8%, respectively. In subjects with average disease duration of 4.1y. The rates of peripheral nerve disorders were 7.7%, Chronic Kidney Disease (CKD) 5%, high levels of albumin in urine 4.3% [5,6].

Epidemiological trials show a connection between various MVCs of DM. E.g., DR is linked to the risk of diabetic nephropathy progression and can predict ischemia and CVD. Moreover, in subjects with T2DM, different MVCs predict CV risk with higher precision than traditional predictors e.g., hypertension, glycated hemoglobin, Lowdensity Lipoprotein Cholesterol (LDL-C), while some MVCs are connected to two-fold higher risk of CVD and CV death [7-9]. These discoveries indicate that screening for MVCs could become a useful instrument to boost CV risk predicting in subjects with DM, as well as that application of CV treatments might help avoid or curb the detrimental CV events [10-12].

MVCs usually progress during years of disease, although the onset can coincide with the moment the individual is diagnosed, especially in case of T2DM. While high blood sugar is a prerequisite for the development of MVCs, the processes underlying the impairment of healthy microvascular structure and functioning are intricate and not fully known [13,14]. Moreover, high blood pressure, reduced LDL-C, high TGs, tobacco use, and DM duration together remarkably affect its pathogenesis. In the past years, the interconnections of genetic and lifestyle factors have been considered a possible way of diabetic MVCs progression. In fact, DR and moderately increased urine albumin are frequently observed in pre-DM and pre-hypertension [15,16].

This review is focused on the development, risk factors, prognoses and preventing of such diabetic MVCs as retinopathy, renal disorders, peripheral neuropathy and autonomic neuropathy. The review also concentrates on the optimal clinical approaches which can be applied to treat individuals with said disorders (Table 1).

Complication Prevention strategy Management / Treatment
Diabetic Retinopathy (DR) Regular screening exams with an ophthalmologist  
  Tight glycemic control  
  Maintain blood pressure <140/80 mmHg Advanced treatments such as Panretinal Photocoagulation (PRP)
Diabetic Nephropathy (DKD) Annual assessment of eGFR and urine albumin levels ACE inhibitors / ARBs for renal protection
  Maintain HbA1c <6.5% Statins for lipid management
Peripheral Neuropathy (PN) Annual foot exams for risk assessment Tight glycemic control
  Patient education on foot care Pain management and physical therapy
Autonomic Neuropathy (AN) Monitor cardiovascular risk factors Cardiovascular autonomic function assessment
  Screening for other diabetic complications Addressing lifestyle factors (diet, exercise)

Table 1: Prevention and Management Strategies for Microvascular Complications (MVCs).

Preventing Microvascular Disease (MVD)

Risk factors: In order to prevent MVD, it is important to monitor exacerbating risk factors and apply screening methods to ameliorate early diagnosis. The UK prospective diabetes study and the diabetes control and complications trial showed that development of DR and diabetic kidney disease is associated with glycemic regulation, as well as that it is vital to retain glycated hemoglobin not higher than 6.5% to alleviate the condition. However, the connection between blood pressure/glucose and diabetic kidney disease is less clear [17,18].

Blood Pressure (BP): The blood pressure should be maintained lower than 140/80 mmHg to avoid development of MVCs. Although, when these levels are reached, it should be further decreased to levels lower than 125/75 mmHg [19,20].

Angiotensin-Converting Enzyme Inhibitors (ACEI): Angiotensin-converting enzyme inhibitors and Angiotensin Receptor Blockers (ARBs) are the treatment of choice. Studies showed their effectiveness in decreasing levels of protein in urine and in suppressing development of kidney failure [21-23]. The Heart outcomes prevention evaluation trial revealed that ramipril decreased evident kidney disease by twenty-four percent [24]. The Reduction of endpoints in NIDDM with the angiotensin II antagonist losartan study showed a twenty-five percent decrease in development of DR and a 28% decrease in the End-stage renal disease risk [25]. Inhibition of angiotensin with angiotensin-converting enzyme inhibitors can also help avoid DR and decrease its severity by fifty percent. Although, these compounds are possibly teratogenic and this should be taken into account when female subjects of reproductive age are treated with it [26,27].

Statins: Diabetic kidney disease can be alleviated with statins which decrease levels of protein in urine and can ameliorate kidney functioning. In subjects with diabetic kidney disease, concentrations of LDL-C should be decreased to be lower than 2 mmol/l. In animal trials, statins have shown an ability to alleviate DR [28-31]. However, results of clinical trials are not as reliable. The Fenofibrate intervention and event lowering in diabetes trial study demonstrated that fibrates have beneficial impact on DR [32].

Screening: MVD has to be detected early with application of reliable screening programs. National screening program for DR began in the nineties and has been crucial for decreasing DM-associated eye diseases [33-35]. Subjects with severe DR should be referred as recommended by national guidelines. Diabetic kidney disease may be detected early by monitoring urine albumin levels, and diabetic nerve disorders can be identified by thoroughly examining lower limbs as part of the annual checkup for subjects with DM [36,37].

Diabetic nephropathy: Diabetic nephropathy is a frequent MVC of diabetes which affects about twenty-five percent of subjects with diabetes. Furthermore, diabetes is one of the main reasons of end-stage renal disease development and it is responsible for a half of the cases. There has been found a connection between presence of albumin in urine and CVD [38,39]. Particularly, moderate elevation of urine albumin concentrations is believed to be a risk factor for cardiovascular disease, whereas treatment which reduces albumin levels has a beneficial impact on CV system. Consistently, early detection and treatment of diabetic nephropathy is vital [40-43].

Diabetic Kidney Disease (DKD) is characterized by changed kidney functioning in subjects with DM, given that other explanations for Chronic kidney disease have been ruled out. Newest ADA’s guidelines state that the diagnosis of diabetic nephropathy should be based on the reduced estimated Glomerular Filtration Rate (eGFR) with levels less than 60 ml/minute/1.73m2 or levels of albumin in urine higher than or equal to 30 mg/g creatinine, which last over three months [44-47].

Since type 2 diabetes is an insidious disease, it is important to check DM subjects for diabetic nephropathy when they are diagnosed and perform annual checkups. The screening has to involve the assessment of estimated glomerular filtration rate following the evaluation of creatinine in serum and the evaluation of Urinary albumin-to-creatinine ratio [48-51].

A number of formulas were suggested for measurement if estimated glomerular filtration rate, among which the CKD Epidemiology Collaboration equation appears to be the most precise. At the early phases of DKD, estimated glomerular filtration rate can be within normal limits or increased because of glomerular hyperfiltration, even though renal functioning is altered. Hereby, more precise markers are needed to determine diabetic nephropathy at early stage and avoid its development [52-56].

Detection of abnormal urinary albumin levels can be conducted by measuring urinary albumin to creatinine ratio or by measuring albumin excreted over a certain amount of time (e.g., twenty-four hours). Evaluation of urinary albumin to creatinine ratio from a spot sample is commonly applied because it is easy and convenient, albeit limited [57,58]. These levels can vary from day to day and the differences may be up to forty percent. Additionally, some disorders can induce an elevation in albuminuria, e.g., Urinary tract infections, pyrexia, Congestive heart failure, hypertension, physical activity, high sugar or protein consumption. Hereby, increased urinary albumin to creatinine ratio needs to be checked again in the following three to six months with two analyses of first-void urine. For diagnosis confirmation, two or three samples must meet the albuminuria criteria. Classic stratification of this condition to micro- and macroalbuminuria were changed lately. In Kidney disease: Improving global outcomes 2012 clinical practice guidelines, this condition is broken down into three groups [59,60]. The first group, A1, is characterized by normal to slightly elevated urinary albumin to creatinine ratio, lower than 30 mg/g creatinine. The second group, A2, is characterized by moderately elevated urinary albumin to creatinine ratio, from 30 to 300 mg/g creatinine. The third group, A3, is characterized by high urinary albumin to creatinine ratio, higher than 300 mg/g creatinine [61-63].

High occurrence rates of type 2 diabetes in adults indicates that not all subjects with DM and changes in renal functioning have diabetic nephropathy, while non-diabetic kidney disease can be accountable for it. Recent research demonstrated that occurrence of non-diabetic kidney disease in subjects with DM varies between 3-82.9%, which could be explained by heterogeneous property of the population [64-67]. Diagnosing DKD requires kidney biopsy, however, it is not often conducted since there are no enough standard criteria. It is mainly preserved for disorders that point to different etiology of CKD. In particular, quickly reducing estimated glomerular filtration rate, active urine sediment, systemic disorders or quickly elevating levels of proteins in urine typically mean that kidney biopsy is necessary [68-70]. Systolic BP, diabetes mellitus duration, diabetic retinopathy and glycated hemoglobin range are in negative correlation with non-diabetic renal disease. Furthermore, decreased estimated glomerular filtration rate with no albuminuria can mean that non-diabetic renal disease is developing [71-74].

Usually, DKD development involves five well-studied phases, drawing on evidence obtained from trials in subjects with T1DM. The initial phase of diabetic nephropathy is hyperfiltration which causes albuminuria, which progresses from micro-albuminuria to macro-albuminuria, with consequent reduction in glomerular filtration rate and increase in BP [75-78]. The advanced stage is end-stage renal failure with negative impact on life quality and a risk of death. Although, recent studies showed that this is not always the case and micro-albuminuria may not develop into macro-albuminuria, and sudden remissions were detected [79,80]. Steno 2 study included more than 7 years of observation and showed that just in 47 patients of 151 macro-albuminuria developed into macro-albuminuria, while 58 patients still had micro-albuminuria and 46 patients had remission [81]. Alleviation of micro-albuminuria is in correlation with anti-hypertension therapy and a reduction in glycated hemoglobin because of ameliorated glucose regulation. At the same time, subjects with DM can exhibit kidney dysfunction with elevated creatinine concentrations, but no albuminuria [82-84]. The United Kingdom prospective diabetes trial showed that in 38% of subjects with DM albuminuria progressed over fifteen years, and kidney dysfunction was observed in 29% of subjects, among which fifty-five percent showed normal levels of urinary albumin [85]. Similar findings were observed in the Renal insufficiency and cardiovascular events study study in 15773 subjects with type 2 diabetes. At baseline, 56.6% of subjects had kidney dysfunction (glomerular filtration rate lower than 60 mL/minute/1.73 m2) and normal levels of albumin, 30.8% of subjects had micro-albuminuria and 12.6% of subjects had macro-albuminuria [86]. Kidney dysfunction with normal levels of albumin was observed in women with reduced glycated hemoglobin, but the connection to diabetic retinopathy and high BP was not as strong in comparison to subjects with albuminuria. It is noteworthy that the occurrence of cardiovascular events in this group of subjects was higher than in subjects with only albuminuria and lower than in subjects with kidney dysfunction and albuminuria (OR 1.66, 1.21 and 2.27 respectively) [87]. Therapy with Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blocker (ARB) and enhanced management of high BP and diabetes are believed to be responsible for the elevated occurrence rates of that phenotype in subjects with DM. Additionally, the probable physiologic mechanism of progression of diabetic nephropathy without albuminuria is macro-angiopathy and not micro-angiopathy. However, recurrent or not resolved AKI could also be responsible for development of that condition [88,89].

Accordingly, estimated glomerular filtration rate and albumin levels are presently utilized markers for diagnosis and observation of diabetic nephropathy. Although, not all chronic kidney disease in subjects with DM can be explained by diabetes. More accurate markers and standard criteria for kidney biopsy are necessary for early diagnosis and treatment of patients with diabetes [90,91].

Diabetic retinopathy

Globally, diabetic retinopathy is the most frequent cause of Vision Impairment (VI). In diabetic retinopathy VI is mostly due to diabetic macular edema, which affects central vision, and proliferative diabetic retinopathy, which causes angiogenesis and dense connective tissue formation which leads to retinal detachment or pre-retinal hemorrhage [92- 95]. Whereas diabetic retinopathy is usually believed to be a primary vascular disease, new evidence indicate that it might be due to DM retinal nerve degeneration. Although, further study is necessary to determine the causality [96- 99].

A meta-analysis of thirty-five studies from 1980 to 2008 was performed and it demonstrated that 25.16% of subjects with type 2 diabetes had diabetic retinopathy, 2.97% had proliferative diabetic retinopathy and 5.57% had diabetic macular edema. Another systematic review showed that global annual occurrence of diabetic retinopathy is from 2.2 to 12.7%, and the development rates vary between 3.4% and 12.3% [100,101].

Blood glucose, BP and lipid levels are well-known diabetic retinopathy risk factors. The UK prospective diabetes study revealed that effective management of blood glucose levels leads to a decrease in MVCs in comparison to traditional therapy. Particularly, there was a twenty-five percent decrease in the risk of the necessity for Panretinal Photocoagulation (PRP) was detected in the glucose management group [102,103]. Another important discovery of that study is that intensive BP control led to a thirty-four percent decrease in the diabetic retinopathy development rates, with 47% decrease in vision impairment. The necessity of PRP was decreased by 35%. The FIELD trial showed that fenofibrate can decrease the necessity for laser therapy for diabetic retinopathy in comparison to the placebo group (3.4% and 4.9%, p=0.0002), mostly because of a decrease in the diabetic macular edema incidence [104- 107]. Beneficial impact of fenofibrate was confirmed in the Action to control cardiovascular risk in diabetes trial [108]. Combined therapy with simvastatin and fenofibrate led to an amelioration in diabetic retinopathy in comparison to the placebo group (6.5% and 10.2%). This study also demonstrated that subjects who underwent tight glucose control showed reduced rates of diabetic retinopathy development in comparison to subjects who were treated with traditional methods (7.3% and 10.4%). Although a correlation between tight BP control and diabetic retinopathy development rates was not found [109,110].

As in DKD, all subjects must be assessed by an ophthalmologist when they are diagnosed with type 2 diabetes. A thorough eye exam is required to find early symptoms of diabetic retinopathy. Ophthalmoscopic examination with dilated fundus enables diagnosis of diabetic retinopathy and determination of its phase [111,112]. Stereoscopic 7F photographs give the same results with the benefit of providing information on subject’s conditions that may be utilized for future comparing. NMDSRI is another accurate instrument which can be applied to evaluate the subjects and detect diabetic retinopathy. However, it is not able to replace thorough eye exam. In subjects with diabetic retinopathy, UWFA may be performed to visualize the vessel leaking, RNP and formation of new blood vessels [113]. OCT is also a useful noninvasive method to assess thickness of the retina, which gives valuable data on the retinal vessels. Additionally, new methods are becoming available, e.g., smartphone fundoscopy. However, the accuracy and precision of this method are yet to be confirmed [114-116].

ADA guidelines suggest to examine the eyes two years in a row, after which the exams can be performed with lower frequency (once in one to three years) provided that the results of the two were normal and the is tight glucose maintenance. In other cases, the time periods are defined by the phase of the disorder to make sure that its development is quickly noticed, since early treatment provides better results [117].

Diabetic retinopathy and Diabetic macular edema classification are drawing on the International clinical diabetic retinopathy disease severity scale severity scale which involves five phases. Diabetic macular edema can be found in any phase of diabetic retinopathy. However, the occurrence rates are higher as diabetic retinopathy develops to advanced stages [118-120]. Diabetic retinopathy is divided into two main groups, non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. Nonproliferative diabetic retinopathy is also broken down into groups: mild non-proliferative diabetic retinopathy, moderate non-proliferative diabetic retinopathy and severe non-proliferative diabetic retinopathy [121-123].

Mild non-proliferative diabetic retinopathy is featured by micro-aneurysms, i.e., bulgings of vascular walls, and retinal dot and blot hemorrhages. Hard exudates are another symptom of this phase of the disease. Such exudates are formed when Lp is leaking from the aneurysms. Subjects with these symptoms must be checked every nine to twelve months [124,125]. As non-proliferative diabetic retinopathy develops, hypoxia of the retina and alterations in circulation can enable serious lesions to be formed. More severe hemorrhages happen, and Intraretinal microvascular abnormalities, venous beadings and Cotton wool spots are typical for advanced phases of non-proliferative diabetic retinopathy [126-128]. In moderate non-proliferative diabetic retinopathy, subjects must be checked every four to six months, and in severe non-proliferative diabetic retinopathy, which involves ischemia and a high risk of proliferative diabetic retinopathy, the subjects must be referred to an ophthalmologist for immediate treatment [129,130].

Diabetic retinopathy develops to the Proliferative diabetic retinopathy, in which formation of new retinal vasculature presents a risk of ruptures, leading to pre-retinal hemorrhage. Such individuals have to be referred to an ophthalmologist to be treated, since there is a high risk of blindness. After the stage of new vessels formation, remission comes with the consequent formation of dense connective tissue and a risk of detachment of the retina [131,132].

To sum up, diabetic retinopathy is a MVC of type 2 diabetes which occurs often. If this condition is not monitored and managed, it will progress into a grave disease. Tight control, examinations by an ophthalmologist and management of risk factors are vital in diabetic retinopathy. Treatments which might abolish the complications of diabetic retinopathy in early phases are scarce, hereby further study is necessary [133].

Diabetic Neuropathy (DN)

Diabetic nerve diseases are pathological conditions that occur in subjects with DM and have various manifestations. This diagnosis is made in subjects with DM and peripheral neuropathy when other diagnoses have been excluded. This MVC of type 2 diabetes occurs often in approximately half of subjects with DM after ten years of living with the disorder [134]. Approximately twenty percent of the subjects with DM already have this complication when they are diagnosed. Although, almost half of the DM subjects with this complication do not show symptoms of it, hereby this MVC is frequently overlooked. When it is not noticed and managed appropriately, it can progress into Charcot arthropathy (diabetic foot), ulcers and a need for amputation [135-137].

A number of classifications were suggested for DN, depending on the anatomical location, prevalence, progression, physiology and properties. Usually, Peripheral DN (DPN) are classified into three groups: symmetric motor polyneuropathy, autonomic and somatic symptoms, focal and multi-focal DN, and combined forms. Recent studies divided peripheral DN into groups: typical peripheral DN, distal symmetric polyneuropathy, and non-typical versions (e.g., MNM, thoracic radiculopathy) [138,139].

Distal symmetric polyneuropathy is the most common form of the complications which constitutes seventyfive percent of all DN. It is a chronic length-dependent condition characterized by symmetry. It can be induced by high blood glucose levels together with CV risk factors [140-142]. No therapies for this condition presently exist that could abolish axonal degeneration and demyelinating of neural tissues, which emphasizes the necessity for early diagnosis which would allow to prevent progression of this MVC [143,144].

Intensive glucose control is believed to be the most important part of the prevention of this MVC. Although, different RCTs showed contradicting results on the distal symmetric polyneuropathy development. The first RCT performed in Japan confirmed that intensive glucose control directly correlated with positive results in context of DN. The same findings were reported in the Accord trial [145,146]. Although, The UK prospective diabetes study could not confirm beneficial impact of tight glucose control on DN. Furthermore, the Veterans affairs diabetes study showed that remarkable difference between glycated hemoglobin levels in intensive and in standard therapies did not lead to different results regarding occurrence of DN [147-149]. Analogously, the Anglo-Danish-Dutch study of intensive treatment in people with screen-detected diabetes in primary care trial involved 5.9 year-long observation and did not demonstrate any considerable differences in the results of two cohorts [150]. It is possible that the two cohorts reached similar levels of glycated hemoglobin by the end of the trial, and the observation period has not been prolonged enough to detect positive impacts. Except glucose control, alterations in life style also could help prevent development of DN. The University of Utah type 2 diabetes study involved subjects with no symptoms of DPN underwent a treatment that included exercise and consumption modifications. Density of Intra-Epidermal Neural Tissues (IENFD) in the lower limb was elevated in this cohort, and it was mildly reduced in the cohort receiving standard treatment. This implies that metabolism amelioration can drive dermal axons to regenerate [151-154].

Similar to other MVCs in type 2 diabetes, such subjects must be evaluated for distal symmetric polyneuropathy when they are diagnosed and then annually checked. NCS are believed to be the best assessment tool for this complication, although its applications in clinical settings are confined and preserved for subjects with non-typical symptoms evident during physical exam [155,156]. Diagnosis of distal symmetric polyneuropathy is mostly clinical. Different neural tissues are involved in distal symmetric polyneuropathy which exhibit various symptoms. In small fibers, the most frequent manifestations are night pain and dysesthesia. There can also be such symptoms as allodynia and hyperalgesia. In large fibers, the most common symptoms are numbness and LOPS [157]. Small fibers are estimated by checking of sensitivity to temperature and pinprick. Large fibers are assessed by measuring sensitivity to vibration, kinesthesia, ankle reflex, sensitivity to light touch. The latter is assessed with application of 10g monofilament, an important instrument to predict risk of ulcers and need for amputation [158-160]. Toronto Consensus Panel (TCP) on DN conducted in 2009 showed that there are four groups of diagnosis certainty drawing on evident manifestations: Possible distal symmetric polyneuropathy, probable distal symmetric polyneuropathy, confirmed distal symmetric polyneuropathy, subclinical distal symmetric polyneuropathy [161,162]. A number of tools were suggested for the assessment of subjects with suspected distal symmetric polyneuropathy, that are mostly foot exam combined with questionnaire. Chronic care management and Intraepidermal nerve fiber density can also be useful for assessment of distal symmetric polyneuropathy. They were validated in clinical studies for evaluation of small fibers, although they have not yet been suggested for routine clinical assessment [163,164].

Distal symmetric polyneuropathy should be diagnosed after exclusion of other DPN etiologies. High alcohol consumption, high blood levels of urea, environmental factors, human immunodeficiency virus, thyroid disorders, paraproteinemia, connective tissue diseases, paraneoplastic neurological disorders and hereditary neural disorders can also induce DPN, and these factors must be excluded with thorough evaluation of family and health history [165,166]. Another study showed that distal symmetric polyneuropathy coincides with different causes of neural disorders in 53% of cases. Hand sensor aberrances in these subjects were detected more often which implies that this symptom might indicate the need to look for other causes of DPN. Most frequent additional symptom in these subjects was excessive alcohol consumption, use of drugs with neurotoxicity, B-12 deficit, and renal disorders [167,168]. Electrodiagnostics and neuraxis magnetic resonance imaging are not commonly applied due to their modest usefulness. Although, these patients should be referred to a neurologist if their symptoms indicate another etiology apart from DN, e.g., fast development, motor neuropathy higher than sensor, non-symmetrical symptoms [169-171].

Diabetes frequently induces autonomic neural disorders with high variety. It has an impact on SNS and PSNS, resulting in inducing various symptoms, e.g., CV, GI, submotor and genitourinary [172].

CV autonomic neuropathy is a well-explored form of DMassociated autonomic neural disorder. It is characterized by impaired CV autonomic regulation, given that other reasons for the condition were excluded. It is present in about sixty percent of subjects with type 2 diabetes fifteen years following the diagnosis [173-175]. It is a major risk factor for CV death and Silent Myocardial Ischemia (SMI). The ACCORD study demonstrated that CV autonomic neuropathy elevated overall mortality by 1.55 to 2.14 times [176]. Tachycardia, aberrant BP regulating, inability to perform physical exercise and postural hypotension are typical signs of this condition, which though often does not show symptoms in early phases. Reduced Heart rate variability is the first sign of cardiovascular autonomic neuropathy, but as the disorder develops, tachycardia and inability to perform physical exercise, postural hypotension, Silent myocardial ischemia and left sided heart failure can progress [177,178].

Screening programs should be applied when a patient is diagnosed with type 2 diabetes, particularly in case of other diabetic MVCs, CV risk factors and high blood sugar present. CV autonomic neuropathy assessment involves Classification and regression trees, heart rate variability, postural HR, Valsalva maneuver HR, standing systolic BP and isometric exercise diastolic BP [179,180]. Time- and frequency domain heart rate variability testing are also good instruments for assessment of cardiovascular autonomic neuropathy. One aberrant cardiovascular autonomic reflex test is enough to diagnose cardiovascular autonomic neuropathy. To confirm the diagnosis, two or three tests should be present [181-183].

Sexual dysfunction

Sexual dysfunction in type 2 diabetes is frequently missed, while it greatly affects life quality. Development of Erectile Dysfunction (ED) in subjects with DM is intricate and involves vascular, neural and hormonal alterations due to diabetes. It represents a manifestation of autonomic DN, micro- and macro-angiopathy. Consistently, erectile dysfunction can probably be used as a biomarker of DMassociated MVCs allowing early treatment [184-186].

Erectile dysfunction is a condition characterized by inability to achieve penile erection of enough durability and rigidity to perform sexual activity. This symptom has to persist for three months or longer to diagnose this disorder. Numerous researches showed that erectile dysfunction occurs in 35 to 90 percent of male patients with DM [187,188]. Such broad range can be explained by variations in methods and populational properties in the researches. Erectile dysfunction occurs three times more frequently in subjects with DM. During ten years after the DM diagnosis, more than a half of subjects with DM exhibit this complication. Another multi-center study involved subjects who were recently diagnosed with type 2 diabetes [189,190]. These subjects were assessed for erectile dysfunction which was observed in one third of the subjects, among which there were mild cases, mild to moderate cases, moderate cases and severe cases (19.4%, 15.4%, 10.4%, 21.6% respectively). These findings emphasize that erectile dysfunction can be a part of early phases of type 2 diabetes [191-193].

Connection between erectile dysfunction and CAD progression is well-known.

Connection between erectile dysfunction and CAD progression is well-known. Erectile dysfunction occurs three to five years prior to the coronary heart disease progression. Hereby, screening programs for erectile dysfunction can provide a possibility to prevent coronary heart disease, particularly in young subjects [194-196]. These discoveries apply to male patients with DM, since erectile dysfunction was validated as a predictor of coronary artery disease in subjects without evident cardiovascular disease. Erectile dysfunction is in correlation with DKD, DR and DN. However, presently there are no ways to apply it as a screening instrument, and more study is required [197,198].

Diagnosis of erectile dysfunction can be made applying questioning. IIEF questionnaire is the most common tool for such diagnostics. It involves fifteen items that explore four main aspects of sexual activity in male subjects: erectile functioning, orgasm functioning, sexual desire and sexual satisfaction. In addition, this can be a useful instrument for evaluation of response to therapy [199-201]. The next stage of evaluation of erectile dysfunction is a thorough review. Diabetes frequently coincides with accompanying disorders which are involved in the erectile dysfunction progression, e.g., high BP, abnormal lipid levels, depression, CVD. Furthermore, alterations of such risk factors as adiposity, lack of exercise, tobacco use, alcohol abuse, can lead to positive results in context of erectile dysfunction [202-204]. In diabetes, occurrence of erectile dysfunction is related to the duration of diabetes, whereas reducing alcohol consumption, inactivity and rest had beneficial effect on erectile functioning. Anti-hypertension and anti-depression drugs can induce erectile dysfunction. Although, such medications are different, and ARBs can exhibit beneficial effect on erectile functioning, but other agents, e.g., Ca2+ antagonists and ACEI do not show such impact [205,206]. Diuretic medications and betablockers can induce erectile dysfunction. Physical exam might not help explain the cause of erectile dysfunction, although, particular signs can be useful for diagnostics, e.g., gynecomastia, changes in patterns of hair growth, absent DP or PT pulses. Subjects with erectile dysfunction have to be evaluated for hypogonadism with application of testosterone tests, since it is often observed in subjects with type 2 diabetes. Approximately twenty percent of male subjects diagnosed with type 2 diabetes have hypogonadism, and as diabetes develops occurrence rates of hypogonadism rise up to fifty percent [207,208].

Specific testing is not typically applied and are preserved for particular cases. Assessment of NPTR tests with application of Rigiscan gives important information on the condition of erectile neural and vascular mechanisms. Duplex ultrasound testing of cavernous arterial circulation following the intracavernosal administration of vasoactive agent can confirm the artery insufficiency. Penile arteries and veins may be investigated following the intracavernosal administration of vasoactive agent. In case of a corporal venoocclusive function impairment, DICC may be applied [209,210].

Female sexual dysfunction is a condition characterized by reduced sexual desire and arousal, painful sexual intercourse and impaired orgasmic function. Recent research demonstrated that female sexual dysfunction occurs more often in subjects with type 2 diabetes in comparison to the control group (OR:2.49). Previous studies showed that in subjects with type 2 diabetes occurrence rates of female sexual dysfunction are from 12 to 88 percent [211-213]. In female subjects with DM depression occurred more often, and body mass index has been the only one parameter that was in correlation with female sexual dysfunction. Female sexual dysfunction can be assessed with application of FSFI, which involves six aspects: Sexual arousal, desire, orgasmic function, vaginal lubrication, intercourse satisfaction, and pain [214,215].

Development of female sexual dysfunction is yet to be fully explored. The risk factors for this condition are not yet identified. Although, female patients with female sexual dysfunction must be screened for type 2 diabetes, since they have higher risk of glucose changes (Table 2).

Complication Prevalence Associated risks Screening recommendations
Diabetic Retinopathy (DR) Affects ~25% of patients with Type 2 DM Higher risk of cardiovascular disease Ophthalmologic exams annually
  Vision impairment    
Diabetic Nephropathy (DKD) Affects ~25% of DM patients Major contributor to End-Stage Renal Disease (ESRD) Annual urine albumin measurement
  Correlates with cardiovascular mortality   eGFR evaluation (annually)
Peripheral Neuropathy (PN) Affects ~50% of DM patients after 10 years Increased risk of foot ulcers, amputations Annual foot exams
Autonomic Neuropathy (AN) ~60% of DM patients within 15 years of diagnosis Silent Myocardial Ischemia (SMI) Autonomic function testing as needed

Table 2: Epidemiological insights on diabetic microvascular complications.

Conclusion

In summary, the staggering rise in diabetes mellitus incidence and its associated microvascular complications underscores the urgent need for comprehensive strategies aimed at prevention, early detection, and effective management. Our review highlights that diabetic retinopathy, nephropathy, peripheral neuropathy, and autonomic neuropathy not only significantly affect patient quality of life but also increase cardiovascular risks. It is crucial to recognize the interconnected nature of these complications, as early identification of one may facilitate the diagnosis and management of others.

Adherence to tight glycemic control, regular screening, and targeted therapeutic interventions such as the use of angiotensin-converting enzyme inhibitors and statins can substantially mitigate the progression of MVCs. Furthermore, lifestyle modifications should be emphasized as integral components in the management of diabetes to enhance patient outcomes.

Ultimately, a multidisciplinary approach involving healthcare providers, patients, and caregivers is essential for optimizing care and empowering individuals with diabetes to manage their health effectively. Future research should aim at refining screening protocols and exploring emerging therapies that can further diminish the burden of microvascular complications. By prioritizing these strategies, we can hope to significantly improve prognosis and quality of life for millions affected by diabetes worldwide.

Funding

This research was funded by Russian Science Foundation, grant number 25-15-0008.

References

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