Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action.

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.

Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.

The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in ß-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

The Wedding Bells Sound Really Good! iGlarLixi Fixed-Ratio Combination in the Treatment of Type 2 Diabetes: A Narrative Review.

iGlarLixi is a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide used in the treatment of type 2 diabetes. iGlarLixi has proven clinical benefits in terms of glycemia, weight control, and safety, defined by the risk of hypoglycemia. It simultaneously targets many pathophysiologic abnormalities which are at the root of type 2 diabetes and thus presents a complementary mode of action. Finally, it may also address diabetes treatment burden, and, by decreasing the complexity of treatment, it may improve patient adherence and persistence and fight against clinical inertia. This article reviews the results of major randomized controlled trials in people with type 2 diabetes that compared iGlarLixi to other therapeutic regimens, representing different intensification strategies, such as basal supported oral therapy, oral antidiabetic drugs, and a combination of the latter with glucagon-like peptide 1 receptor agonists. Moreover, as a supplement to randomized trials, data from real-world evidence have also been included.

Novel methods of continuous glucose monitoring and telehealth in the improvement of diabetes care: a narrative review.

Standard markers of glycaemic control, such as glycated haemoglobin (HbA1c) and self-measurement of blood glucose (SMBG), have proven insufficient. HbA1c is an averaged measurement that does not give information about glucose variability. SMBG provides limited, intermittent blood glucose (BG) values over the day and is associated with poor compliance because of the invasiveness of the method and social discomfort. In contrast to glucometers, continuous glucose monitoring (CGM) devices do not require finger-stick blood samples, but instead measure BG via percutaneous or subcutaneous sensors. The immediate benefits of CGM include prevention of hypoglycaemia or hyperglycaemia, and automated analysis of long-term glycaemic data enables reliable treatment adjustments. This review describes the principles of CGM and how CGM data have changed diabetes treatment standards by introducing new glycaemic control parameters. It also compares different CGM devices and examines how the convenience of sharing CGM data in telehealth applies to the current coronavirus-19 pandemic.

Intermittent Use of Continuous Glucose Monitoring: A New Paradigm in Treatment of Type 2 Diabetes.

OBJECTIVES: To suggest how continuous glucose monitoring (CGM) may be used intermittently in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The use of CGM is largely in those with type 1 diabetes (T1D), in whom it makes sense to use CGM continuously as CGM provides a valuable tool to not only adjust their insulin doses but also to match it with their diet, physical activity, and other lifestyle modifications. In the case of T2D, however, especially for those not on insulin, the use of CGM may not be needed on a continuous basis. The use of CGM on an intermittent basis is rarely discussed in the literature. This article tries to provide clinical situations where CGM can be used intermittently. RESULTS: Intermittent use of CGM defined as the "use of CGM once in 2 or 3 months or a fixed frequency," and may be useful in several situations in those with T2D. We suggest the following indications for the intermittent use of CGM in T2D-newly diagnosed patients where treatment is being started, uncontrolled diabetes where treatment is being altered, starting intensive lifestyle modification, during infections, during preoperative control, in children and adolescents with T2D, as a motivational tool to improve behavioral modification, after metabolic surgery, and in patients on steroids, apart from other indications. CONCLUSION: Intermittent use of CGM in T2D can be useful in special situations and can also be cost saving particularly in resource-constrained regions of the world.

Expanding the Role of Continuous Glucose Monitoring in Modern Diabetes Care Beyond Type 1 Disease.

Application of continuous glucose monitoring (CGM) has moved diabetes care from a reactive to a proactive process, in which a person with diabetes can prevent episodes of hypoglycemia or hyperglycemia, rather than taking action only once low and high glucose are detected. Consequently, CGM devices are now seen as the standard of care for people with type 1 diabetes mellitus (T1DM). Evidence now supports the use of CGM in people with type 2 diabetes mellitus (T2DM) on any treatment regimen, not just for those on insulin therapy. Expanding the application of CGM to include all people with T1DM or T2DM can support effective intensification of therapies to reduce glucose exposure and lower the risk of complications and hospital admissions, which are associated with high healthcare costs. All of this can be achieved while minimizing the risk of hypoglycemia and improving quality of life for people with diabetes. Wider application of CGM can also bring considerable benefits for women with diabetes during pregnancy and their children, as well as providing support for acute care of hospital inpatients who experience the adverse effects of hyperglycemia following admission and surgical procedures, as a consequence of treatment-related insulin resistance or reduced insulin secretion. By tailoring the application of CGM for daily or intermittent use, depending on the patient profile and their needs, one can ensure the cost-effectiveness of CGM in each setting. In this article we discuss the evidence-based benefits of expanding the use of CGM technology to include all people with diabetes, along with a diverse population of people with non-diabetic glycemic dysregulation.

Allogenic Adipose-Derived Stem Cells in Diabetic Foot Ulcer Treatment: Clinical Effectiveness, Safety, Survival in the Wound Site, and Proteomic Impact.

Although encouraging results of adipose-derived stem cell (ADSC) use in wound healing are available, the mechanism of action has been studied mainly in vitro and in animals. This work aimed to examine the safety and efficacy of allogenic ADSCs in human diabetic foot ulcer treatment, in combination with the analyses of the wound. Equal groups of 23 participants each received fibrin gel with ADSCs or fibrin gel alone. The clinical effects were assessed at four time points: days 7, 14, 21 and 49. Material collected during debridement from a subset of each group was analyzed for the presence of ADSC donor DNA and proteomic changes. The reduction in wound size was greater at all subsequent visits, significantly on day 21 and 49, and the time to 50% reduction in the wound size was significantly shorter in patients who received ADSCs. Complete healing was achieved at the end of the study in seven patients treated with ADSCs vs. one treated without ADSCs. One week after ADSC application, 34 proteins significantly differentiated the material from both groups, seven of which, i.e., GAPDH, CAT, ACTN1, KRT1, KRT9, SCL4A1, and TPI, positively correlated with the healing rate. We detected ADSC donor DNA up to 21 days after administration. We confirmed ADSC-related improvement in wound healing that correlated with the molecular background, which provides insights into the role of ADSCs in wound healing-a step toward the development of cell-based therapies.

Indirect insulin resistance markers are associated with nonalcoholic fatty liver disease in type 1 diabetes.

INTRODUCTION: Insulin resistance (IR) in type 1 diabetes mellitus (T1DM) is associated with increased insulin dose requirements, poor glycemic control, and elevated risk of chronic complications. IR increases lipid synthesis and hepatic lipid content. Disruption in hepatic lipid accumulation and export leads to liver steatosis resulting in nonalcoholic liver disease (NAFLD). OBJECTIVES: The aim of the study was to explore the relationship between indirect IR markers and NAFLD in T1DM. PATIENTS AND METHODS: We analyzed 151 patients with T1DM (59 men, 92 women), with a median (interquartile range [IQR]) age of 40 (33-47) years and a median (IQR) diabetes duration of 19 (13-21)years. The median (IQR) value of glycated hemoglobin (HbA1c) was 7.5% (6.8%-8.%; 58 [51-66] mmol/mol). The following indirect IR markers were evaluated: estimated glucose distribution rate (eGDR), visceral adiposity index (VAI), and the triglyceride to high­density lipoprotein cholesterol ratio (TG/HDL­C). Fatty infiltration of the liver was quantified using transient elastography. Presence of NAFLD was defined as a controlled attenuation parameter value of 238 dB/m or greater. RESULTS: NAFLD was observed in 65 patients (43%). The participants with NAFLD were less insulin­sensitive (eGDR, 8.93 [6.39-9.97] vs 9.94 [8.09-11.13] mg/kg/min; P = 0.001; VAI, 1.52 [1.2-2.64] vs 1.34 [0.92-1.74]; P = 0.014; TG/HDL­C ratio, 1.35 [0.95-2.11] vs 1.11 [0.77-1.6]; P = 0.02) and were characterized by higher HbA1c values (7.75% [7.2%-8.4%] vs 7.3% [6.5%-8.1%]; 61 [55-68] vs 56 [48-65] mmol/mol; P = 0.02) than the patients without the disease. In a multivariable regression analysis adjusted for sex, diabetes duration, and HbA1c level, indirect IR markers were independently associated with NAFLD (eGDR: odds ratio [OR], 0.86; 95% CI, 0.77-0.97; P = 0.01; VAI: OR, 1.61; 95% CI, 1.05-2.49; P = 0.03, TG/HDL­C ratio: OR, 1.88; 95% CI, 1.11-3.18; P = 0.02). CONCLUSIONS: In T1DM, NAFLD is more likely to be found in individuals with lower insulin sensitivity.

Getting them through the door: Social and behavioral determinants of uptake and engagement in an obesity intervention.

Using data from a large-scale screening program (N = 19634), we aimed to prospectively identify factors predicting uptake (i.e. acceptance of the invitation) and engagement (i.e. participation in at least two sessions) in a multi-component-intensive-behavioral-intervention for obesity-management (MBIOM) intervention targeting adolescents (n = 2862; 12-14 years; BMI ≥90th percentile). Approximately one third of adolescents most in need of weight management declined the initial invitation to enter the MBIOM. Poor diet, sedentary behavior, and parental education predicted willingness to enter and stay in the intervention, however measured body mass index did not matter. Perceived family support, instead of initial motivation, facilitated engagement. Our results provide new insights on the importance of regional socio-geographical factors including trust in local authorities.

[Association of antithyroid peroxidase antibodies with cardiac function in euthyroid women with type 1 diabetes mellitus - assessment with two-dimensional speckle­tracking echocardiography].

INTRODUCTION: The presence of diabetes is associated with loss of cardioprotection in premenopausal women; however, the mechanisms involved remain unknown. Autoimmune factors are suspected to play a role in cardiovascular complications, especially in type 1 diabetes (T1DM). The aim of this pilot study was to explore whether antithyroid peroxidase antibody (aTPO) as a marker of increased immune activity is related to cardiac dysfunction in young, asymptomatic women with T1DM. MATERIAL AND METHODS: Eighty-eight euthyroid women (59 with T1DM and 29 healthy controls) underwent physical examination, laboratory tests, thyroid ultrasound, and two-dimensional speckle-tracking echocardiography. According to the antiperoxidase antibodies (aTPO) titre, the T1DM women were divided into an aTPO positive (T1DM aTPO+) (n = 34) and an aTPO negative (T1DM aTPO-) (n = 25) group. The relationship between thyroid autoimmunity parameters and echocardiographic parameters was evaluated. RESULTS: Global longitudinal strain (GLS) was slightly reduced in the T1DM aTPO+ group compared to T1DM aTPO- and significantly compared to controls (p = 0.051 and p = 0.015, respectively). Although, the lower values of longitudinal strain of left ventricular were found in the majority of segments in the T1DM aTPO+ group in comparison to T1DM aTPO- and controls, significant differences were only found in the two-chamber view (specifically in the anterior segments) between the T1DM aTPO+ and T1DM aTPO- groups (p = 0.030) and in the four-chamber view (specifically in the anterolateral segments) between the T1DM aTPO+ group and controls (p = 0.021). Echocardiographic parameters of diastolic and systolic function of both ventricles were significantly correlated with parameters of thyroid autoimmunity. A logistic regression analysis showed that Hashimoto's thyroiditis (HT) duration [odds ratio (OR): 0.997, 95% confidence interval (CI): 0.995-0.999, p = 0.008), the dose of levothyroxine (OR: 0.814, 95% CI: 0.689-0.960, p = 0.013), and reduced echogenicity on thyroid ultrasound (OR: 0.309, 95% CI: 0.120-0.793, p = 0.013) had a significant influence on reduced GLS. CONCLUSIONS: Our results suggest that coexistence of aTPO with T1DM was associated with poorer myocardial function, particularly in the anterior and anterolateral segments, which may be related to an autoimmune factor. The impaired function of these segments is probably the first sign of myocardial systolic dysfunction in women with T1DM, which needs to be confirmed in further studies.

The Problem of Wound Healing in Diabetes-From Molecular Pathways to the Design of an Animal Model.

Chronic wounds are becoming an increasingly common clinical problem due to an aging population and an increased incidence of diabetes, atherosclerosis, and venous insufficiency, which are the conditions that impair and delay the healing process. Patients with diabetes constitute a group of subjects in whom the healing process is particularly prolonged regardless of its initial etiology. Circulatory dysfunction, both at the microvascular and macrovascular levels, is a leading factor in delaying or precluding wound healing in diabetes. The prolonged period of wound healing increases the risk of complications such as the development of infection, including sepsis and even amputation. Currently, many substances applied topically or systemically are supposed to accelerate the process of wound regeneration and finally wound closure. The role of clinical trials and preclinical studies, including research based on animal models, is to create safe medicinal products and ensure the fastest possible healing. To achieve this goal and minimize the wide-ranging burdens associated with conducting clinical trials, a correct animal model is needed to replicate the wound conditions in patients with diabetes as closely as possible. The aim of the paper is to summarize the most important molecular pathways which are impaired in the hyperglycemic state in the context of designing an animal model of diabetic chronic wounds. The authors focus on research optimization, including economic aspects and model reproducibility, as well as the ethical dimension of minimizing the suffering of research subjects according to the 3 Rs principle (Replacement, Reduction, Refinement).

Translating results from the cardiovascular outcomes trials with glucagon-like peptide-1 receptor agonists into clinical practice: Recommendations from a Eastern and Southern Europe diabetes expert group.

Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.

[Is thyroid autoimmunity associated with subclinical atherosclerosis in young women with type 1 diabetes mellitus?]

INTRODUCTION: It has been hypothesized that autoimmunity may contribute to cardiovascular complications and may be an important trigger for processes leading to atherosclerosis, especially in type 1 diabetes mellitus (T1DM). This pilot study aimed to answer the question of whether markers of thyroid autoimmunity are associated with increased carotid intima-media thickness (cIMT) in young, asymptomatic T1DM women. MATERIAL AND METHODS: The study population consisted of 102 women, including 72 with T1DM and 30 healthy controls. All patients had thyroid hormones within the normal range. According to the antiperoxidase antibodies (aTPO) titre, the T1DM women were divided into an aTPO-positive (T1DM aTPO+) (n = 41) and an aTPO-negative (T1DM aTPO-) (n = 31) group. In all patients, aTPO, thyroglobulin antibody (aTG) titres, thyroid-stimulating hormone (TSH), free thyroxine (FT3), free triiodothyronine (FT4), lipid parameters, glycated haemoglobin, thyroid ultrasonography, and cIMT assessment were evaluated. The association of cIMT with different risk factors related to thyroid autoimmunity was determined. RESULTS: Carotid intima-media thickness was significantly greater in T1DM aTPO+ females (0.66 ± 0.10 mm) than in T1DM aTPO- (0.59 ± 0.11 mm) and healthy controls (0.58 ± 0.10 mm) (p = 0.007, p = 0.001, respectively). In all women cIMT was significantly, positively correlated with aTPO (p = 0.005, r = 0.273), Hashimoto's thyroiditis (HT) duration (p = 0.00015, r = 0.367), levothyroxine dose per week (p = 0.006, r = 0.269), and ultrasound features of HT (p = 0.004, r = 0.281) and inversely with fT3 concentration (p = 0.014, r = -0.243) and FT3/FT4 ratio (p = 0.042, r = -0.201). A logistic regression analysis showed that HT duration (OR: 1.102, 95% CI: 1.008-1.206, p = 0.032) and a positive history family of HT (OR: 3.909, 95%CI: 1.014-15.071, p = 0.045) were risk factors for increased cIMT. However, multivariate regression analysis showed that the studied parameters related to thyroid autoimmunity are not independent risk factors for increased cIMT. CONCLUSIONS: We expanded the data on cIMT in young women with T1DM and showed that thyroid autoimmunity, and in particular the duration of exposure to anti-thyroid antibodies, despite adequate levothyroxine substitution, is associated with subclinical atherosclerosis in young women with T1DM. However, thyroid-related parameters are not independent risk factors for increased cIMT in euthyroid women.

Fitness, Food, and Biomarkers: Characterizing Body Composition in 19,634 Early Adolescents.

Adolescent obesity persists as a major concern, especially in Central and Eastern Europe, yet evidence gaps exist regarding the pivotal early adolescent years. Our objective was to provide a comprehensive picture using a holistic approach of measured anthropometry in early adolescence, including body composition, cardiorespiratory fitness (CRF), and reported lifestyle characteristics. We aimed to elucidate potential sex/gender differences throughout and associations to biomarkers of disease risk for obese adolescents. Methods: Trained nurses measured 19,634 early adolescents (12−14-year-olds), we collected parental reports, and, for obese adolescents, fasting blood samples in four major Polish cities using a cross-sectional developmental design. Results: 24.7% boys and 18.6% girls were overweight/obese, and 2886 had BMI ≥ 90th percentile. With increasing age, there was greater risk of obesity among boys (p for trend = 0.001) and a decreasing risk of thinness for girls (p for trend = 0.01). Contrary to debate, we found BMI (continuous) was a useful indicator of measured fat mass (FM). There were 38.6% with CRF in the range of poor/very poor and was accounted for primarily by FM in boys, rather than BMI, and systolic blood pressure in girls. Boys, in comparison to girls, engaged more in sports (t = 127.26, p < 0.0001) and consumed more fast food (t = 188.57, p < 0.0001) and sugar-sweetened beverages (167.46, p < 0.0001). Uric acid, a potential marker for prediabetes, was strongly related to BMI in the obese subsample for both boys and girls. Obese girls showed signs of undernutrition. Conclusion: these findings show that overweight/obesity is by far a larger public health problem than thinness in early adolescence and is characterized differentially by sex/gender. Moreover, poor CRF in this age, which may contribute to life course obesity and disease, highlights the need for integrated and personalized intervention strategies taking sex/gender into account.

Breakdown of Diabetic Foot Ulcer Care during the First Year of the Pandemic in Poland: A Retrospective National Cohort Study.

The COVID-19 pandemic revealed a breakdown of the system of DFU patient care. This retrospective national cohort study analyses the epidemiological status of DFU patients in relation to urgent and elective hospitalizations, amputation rates, and deaths in Poland from 2017 to 2019, and during 2020 when the COVID-19 pandemic began. The data were obtained from national medical records gathered by the National Health Fund (NHF). Discharge diagnoses were categorized according to ICD-10 and ICD-9 codes. Analysis of the data showed a statistically significant decrease in elective hospital admissions (from 29.6% to 26.3%, p = 0.001). There was a decrease in the percentage of hospitalizations related to limb-salvage procedures (from 79.4% to 71.3%, p = 0.001). The opposite tendency was observed among urgent hospital admissions (from 67.0% to 73.2%, p = 0.01), which was related to a significant increase in the number of minor amputations (from 3146 to 4269, p = 0.017). This rise was in parallel with the increase in the percentage of patients who died during hospitalization due to DFU (from 3.9% to 4.8%, p = 0.03). The number of deaths has not changed significantly (from 590.7 to 668.0, p = 0.26). The results of the conducted analyses confirm the negative tendencies in the medical care of patients with DFU during the first year of the pandemic in Poland. Changes in therapy schemes and stronger patient support following this period are necessary to avoid further complications in patients with DFU.

Ambulatory Glucose Profile (AGP) Report in Daily Care of Patients with Diabetes: Practical Tips and Recommendations.

The ambulatory glucose profile (AGP) is now established as the standardised, practical one-page report for graphically presenting a summary of glycaemic control status in patients with diabetes who use continuous glucose monitoring (CGM) systems as part of their daily diabetes care. The AGP report provides both a visual and a statistical summary of the glucose metrics that, as agreed in the 2019 international consensus for assessing glycaemic control, should be analysed in all people with diabetes who are using CGM systems. The AGP report can be analysed in a systematic fashion to understand current glycaemic control and to monitor, in real time, the impact of adjustments to therapy in both type 1 diabetes and type 2 diabetes. Here we provide a practical guide to the glycaemic measures that are summarised in the AGP Report and illustrate the essential components of an AGP review in a series of hypothetical, real-world, patient-centred case studies (see Supplementary Materials).

Chronic Diabetic Complications: Current Challenges and Opportunities.

The Special Issue, "Chronic Diabetic Complications: Current Challenges and Opportunities", is rich in scientific content, covering a wide field of diabetic complications via both original studies and reviews [...].