Search Results (1,009)

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and accumulation of harmful lipid species contribute to cellular stress, mitochondrial injury, inflammation, and fibrosis. In parallel, disordered lipid handling in the vasculature promotes endothelial dysfunction and atherosclerotic plaque development. However, not all lipid accumulation appears to be detrimental, and some findings suggest adaptive or context-dependent effects, leading to inconsistent results across studies. In this review, we summarize current evidence on lipid metabolism in diabetic nephropathy and atherosclerosis, compare shared and distinct features, and discuss ongoing controversies. We also briefly address the therapeutic relevance of targeting lipid pathways and highlight areas that require further investigation. Compared with prior reviews that mainly discussed fatty kidney as an emerging concept in chronic kidney disease research, this review specifically focuses on diabetic kidney disease and integrates kidney-specific lipid trafficking, kidney–vessel crosstalk, conflicting evidence, and mechanism-based therapeutic implications. Full article

Background: Ectopic fat deposition has been demonstrated to play a critical role in the onset and progression of renal dysfunction. However, research on renal parenchymal fat deposition and its association with renal dysfunction in type 2 diabetes mellitus (T2DM) remains limited, particularly regarding its association with early kidney injury. The present study aimed to further investigate the relationship between renal fat fraction (FF) and biomarkers of kidney injury, thereby providing new evidence for the potential link between intrarenal fat accumulation and early renal impairment in T2DM. Methods: This cross-sectional study enrolled 60 patients with T2DM. Renal FF was quantitatively assessed using magnetic resonance imaging (MRI). Clinical characteristics, body composition parameters, and biochemical indices were collected. Levels of kidney injury biomarkers, including tumor necrosis factor receptors 1 (TNF-R1), tumor necrosis factor receptors 2 (TNF-R2), chitinase-3-like protein 1 (YKL-40), and kidney injury molecule-1 (KIM-1), were measured using enzyme-linked immunosorbent assay (ELISA). To evaluate the correlations between fat distribution and inflammatory biomarkers, Pearson correlation analysis was performed. Furthermore, linear regression analysis was conducted to explore the associations between renal FF and kidney injury biomarkers with adjustments for potential confounders such as smoking status, diabetes duration, and visceral fat. Lasso regression was used to screen variables. Results: The results demonstrated that renal FF was significantly positively correlated with serum YKL-40 (r = 0.3, p = 0.021), TNF-R1 (r = 0.246, p = 0.042), and urinary KIM-1 (r = 0.396, p = 0.004), indicating a close association between renal fat accumulation and early kidney injury biomarkers. In regression analyses adjusted for age, sex, and duration of diabetes, the associations between renal FF and these biomarkers remained significant. After further adjustment for potential confounders, including smoking history, alcohol consumption, hypertension, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, glucagon-Like Peptide-1 (GLP-1) receptor agonists, and lipid-lowering drugs, renal FF remained significantly associated with TNF-R1 (β = 0.327, p = 0.015), KIM-1 (β = 0.352, p = 0.021), and YKL-40 (β = 0.275, p = 0.025). Moreover, even after additional adjustment for visceral fat, the associations of renal FF with TNF-R1 and KIM-1 persisted. After using the Benjamini–Hochberg procedure for false discovery rate, the relationship between renal FF and KIM-1 had a significant difference. Variables of age and gender were excluded to build the parsimonious modeling using Lasso regression. It suggested that renal fat accumulation may contribute to kidney injury independently of visceral adiposity. Conclusions: The study systematically demonstrates a significant association between renal FF and early biomarkers of kidney injury in T2DM, which may suggest the potential role of renal fat accumulation in the pathogenesis of diabetic nephropathy. These findings provide clinical data support for the development of a fat-targeted intervention study. Future research should further elucidate the long-term mechanistic role of renal FF in diabetic nephropathy, as well as its potential value in early diagnosis and therapeutic applications. Full article

Background: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine associated with inflammation, metabolic dysfunction, and cardiovascular disease. Its role as a biomarker of microvascular complications in type 2 diabetes (T2D) remains incompletely defined. Objective: To evaluate circulating GDF-15 levels and their association with microvascular complications in patients with T2D. Methods: This cross-sectional study included 160 participants divided into three groups: T2D (n = 93), obesity without carbohydrate disorders (n = 36), and healthy controls (n = 31). Microvascular complications (neuropathy, nephropathy, retinopathy) were assessed. Multivariable logistic regression and receiver operating characteristic (ROC) analysis were performed. Results: GDF-15 levels were significantly higher in T2D compared with non-diabetic individuals (267.5 ± 168.9 vs. 118.3 ± 55.5 pg/mL, p < 0.001). Higher GDF-15 was associated with neuropathy (odds ratio (OR) 1.985; 95% confidence interval (CI) 1.431–2.753) and nephropathy (OR 1.673; 95% CI 1.243–2.254) in unadjusted models. After adjustment, only nephropathy remained independently associated (OR 1.405; 95% CI 1.026–1.923). ROC analysis showed moderate discriminative ability for nephropathy (area under the curve (AUC) = 0.763). Conclusions: Circulating GDF-15 levels are significantly elevated in patients with T2D and are associated with microvascular complications, with the strongest independent association observed for diabetic nephropathy. These findings suggest that GDF-15 may represent a promising biomarker reflecting metabolic stress and risk of diabetic complications. Full article

Background: The endothelial activation and stress index (EASIX), derived from the serum lactate dehydrogenase, creatinine, and platelet counts, is a composite biomarker for endothelial dysfunction and systemic stress. It has been developed to predict clinical outcomes in hematologic malignancies. This study aimed to investigate the EASIX’s predictive role in contrast-induced nephropathy (CIN) and in-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods: A total of 1552 patients with STEMI who underwent primary PCI were retrospectively included. The patients were divided into two groups: CIN (+) and CIN (−). Baseline demographic, laboratory, clinic, and procedural variables were compared between the two groups. Logistic regression analysis was performed to identify independent predictors of CIN and in-hospital mortality, while receiver operating characteristic (ROC) curves were used to determine the optimal EASIX cut-off values. Results: CIN developed in 7.6% (n = 118) of the study population, and these patients had significantly increased EASIX scores. Those with CIN were older and exhibited higher rates of diabetes mellitus, chronic kidney disease (CKD), and decreased left ventricular ejection fraction (LVEF) (all p < 0.001). In multivariable analysis, age (OR 1.053), CKD (OR 1.338), reduced LVEF (OR 0.965), and EASIX (OR 2.467) independently predicted CIN. EASIX > 0.93 demonstrated strong discriminatory ability (AUC 0.785; sensitivity 72% and specificity 72%). EASIX also independently predicted in-hospital mortality (OR 3.592), with an optimal cut-off > 0.88 (AUC 0.774). Conclusions: By integrating markers of renal function, endothelial activation, and systemic stress, EASIX may serve as a useful and reliable indicator for predicting CIN development and in-hospital mortality in STEMI patients undergoing primary PCI. Full article

Objectives: To investigate the effects of Roxadustat and recombinant human erythropoietin (rHuEPO) on glycemic control and glycated hemoglobin (HbA1c) in non-dialysis type 2 diabetic kidney disease (DKD) patients with anemia. Methods: This retrospective study enrolled 449 patients, who were divided into three groups—the rHuEPO group (n = 252), the Roxadustat group (n = 102), and the switch group (n = 95)—in which patients were converted from rHuEPO to Roxadustat. All treatments lasted for more than three months. Changes in HbA1c and other indicators within groups as well as differences among groups were evaluated. Results: In the rHuEPO group, HbA1c levels decreased from 7.08 ± 1.19 to 6.41 ± 0.60 (p < 0.001), and they returned to baseline levels by 6–12 months (p > 0.05). In the Roxadustat group, HbA1c fluctuated but none of the differences reached statistical significance (p > 0.05). In the switch group, HbA1c decreased during rHuEPO treatment (p < 0.05) and returned to baseline after switching to Roxadustat (p > 0.05). No significant changes in blood glucose levels were observed in any group after treatment (p > 0.05). Multivariate linear regression analysis showed that changes in iron metabolism parameters, erythrocyte parameters, inflammatory markers, and glucose-lowering or lipid-lowering regimens had no significant effect on the change in HbA1c in the Roxadustat group (F = 0.834, p = 0.620), while the multivariate model of rHuEPO group also lacked statistical significance (F = 1.142, p = 0.170). After treatment, all three groups showed improvements in anemia, iron metabolism, renal function, inflammatory markers, and lipid profiles compared with baseline (p < 0.05). Additionally, further improvements in these parameters were observed after the transition from rHuEPO to Roxadustat (p < 0.05). Compared with rHuEPO group, the Roxadustat group exhibited significantly greater increases in hemoglobin, red blood cell count, total iron-binding capacity, transferrin, and serum iron (p < 0.05). Conclusions: In non-dialysis DKD patients with anemia, rHuEPO can significantly decrease HbA1c values, while Roxadustat does not. Roxadustat offers advantages over rHuEPO in terms of efficacy and assessment of glycemic control. Full article

Background: Diabetic nephropathy (DN), also referred to as diabetic kidney disease, represents one of the most common microvascular complications of type 2 diabetes mellitus (T2DM) and remains a leading cause of end-stage renal disease worldwide. Conventional clinical markers, including albuminuria and estimated glomerular filtration rate (eGFR), are widely used for diagnosis and staging but may have limited sensitivity for detecting early renal injury and predicting disease progression. In recent years, circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers that reflect underlying molecular mechanisms of diabetic nephropathy and may complement traditional clinical indicators. Objective: The present study aimed to evaluate serum and urinary levels of hsa-miRNA-770-5p across different stages of diabetic nephropathy and to assess its potential diagnostic value in relation to established indicators of renal function. Methods: A total of 257 participants were included and divided into four groups: healthy controls, patients with T2DM without nephropathy, patients with T2DM and DN in CKD stages I–II, and patients with DN undergoing maintenance hemodialysis (MHD). Serum and urinary levels of miRNA-770-5p were measured using quantitative real-time polymerase chain reaction (qPCR) and analyzed using the 2^−ΔΔCt method. Statistical analyses included comparisons between groups using ANOVA, correlation analyses with renal function parameters such as eGFR and proteinuria/albuminuria, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic performance. Results: Serum levels of miRNA-770-5p were significantly elevated in patients with DN and in patients undergoing maintenance hemodialysis compared with healthy controls and patients with T2DM without nephropathy. In contrast, urinary levels of miRNA-770-5p were markedly reduced in patients with DN. Serum levels in patients with T2DM without nephropathy were slightly lower than those observed in healthy controls. Significant correlations were identified between miRNA-770-5p levels and renal function parameters, including eGFR and proteinuria/albuminuria, supporting the biological relevance of this microRNA in renal injury. ROC curve analysis demonstrated good discriminatory ability for differentiating DN from T2DM without nephropathy (serum AUC = 0.82; urine AUC = 0.79). Conclusions: hsa-miRNA-770-5p demonstrates distinct and opposite patterns in serum and urine that correlate with the severity of diabetic nephropathy. The complementary changes observed in circulating and urinary levels support the potential of miRNA-770-5p as a non-invasive biomarker that may complement conventional clinical markers and provide additional insight into the molecular mechanisms involved in the development and progression of diabetic nephropathy. Full article

Background: The primary aim of pancreas transplantation in type 1 diabetic kidney transplant recipients is to reduce mortality caused by complications of progressing cardiovascular diseases and to protect kidney graft from the recurrence of diabetic nephropathy. The aim of this study was to analyze the results of the first deceased donor kidney transplantation (KTx) in patients with end-stage kidney disease caused by long-lasting type 1 diabetes (T1D), performed alone or simultaneously with the pancreas (SPK), in a long-term follow-up period. Methods: Groups of 101 consecutive T1D patients after KTx and 93 patients after SPK performed in two transplant centers with a minimal follow-up period of 5 years were included in the analysis. Results: Recipient, kidney graft, and death-censored kidney graft survival in a follow-up period of up to 20 years did not differ between KTx and SPK groups. In the entire observation period, total diabetes duration was shorter in the SPK group compared to KTx (28.1 ± 7.4 vs. 34.9 ± 11.0 years), and myocardial infarction (21 vs. 7%), limb amputation (12 vs. 3%), and proteinuria (40 vs. 18%) were more common in the KTx group than in SPK. The estimated glomerular filtration rate was lower in KTx recipients compared to SPK. Recipient survival was affected by the recipient’s age and the duration of dialysis vintage, and kidney graft survival was affected by the duration of dialysis vintage, episodes of acute rejection, and high pretransplant sensitization in patients. Conclusions: Despite reduced diabetes duration, a decreased frequency of cardiovascular disease complications and better kidney graft function, a simultaneously transplanted pancreas does not improve patient or kidney graft survival in T1D kidney recipients. Full article

Background: Chronic low-grade inflammation plays a central role in the pathogenesis of type 2 diabetes (T2DM) and its complications. Neopterin, a marker of macrophage activation and Th1-mediated immune response, has been associated with cardiovascular disease and metabolic disorders. However, its relationship with diabetic autonomic neuropathy remains insufficiently investigated. Methods: We conducted a cross-sectional study including 129 participants (93 with T2DM and 36 with obesity without carbohydrate disturbances). Clinical, anthropometric, and biochemical assessments were performed. Cardiovascular autonomic neuropathy was evaluated using Ewing cardiovascular reflex tests and sudomotor dysfunction scoring. Neopterin concentrations were measured in serum. Correlation, ROC, and logistic regression analyses were performed. Results: Neopterin levels were not significantly different between T2DM and obesity groups. No differences were observed in patients with versus without peripheral neuropathy, nephropathy, or retinopathy. However, neopterin levels were significantly higher in individuals with cardiovascular autonomic neuropathy (p = 0.013). Neopterin correlated with cardiovascular autonomic neuropathy score, sudomotor dysfunction, fasting glucose, fasting insulin, and HOMA-IR. It showed a moderate negative monotonic correlation with eGFR (Spearman’s rho = −0.41, p< 0.001). In multivariable logistic regression adjusted for age, HbA1c, BMI, eGFR, and diabetes duration, each 1-SD increase in neopterin was associated with 2.67-fold higher odds of cardiovascular autonomic neuropathy (95% CI 1.21–5.89; p = 0.015). Conclusions: Circulating neopterin is independently associated with cardiovascular autonomic neuropathy in T2DM but not with classical microvascular complications. These findings suggest a potential role of immune-mediated mechanisms in the pathogenesis of diabetic cardiovascular autonomic neuropathy. Full article

Background: The aim of our study was to evaluate the association of angiopoietin 2 (ANGPT2) rs2442598 and vascular endothelial growth factor A (VEGFA) rs2010963 with diabetic nephropathy (DN) in Slovenian subjects with type 2 diabetes mellitus (T2DM). Angiopoietin–endothelial tyrosine kinase receptor (Ang-Tie2) and VEGF-A signaling regulate glomerular endothelial stability and permeability and may contribute to DN susceptibility. Methods: We conducted a case–control study including 897 unrelated Slovenian subjects with T2DM (344 DN cases; 553 long-standing T2DM controls without DN). ANGPT2 rs2442598 and VEGFA rs2010963 were genotyped using TaqMan assays. Genetic associations were analysed using co-dominant, additive, dominant, and recessive genetic models with logistic regression adjusted for waist circumference, systolic blood pressure, fasting glucose, and triglycerides. Results: ANGPT2 rs2442598 was significantly associated with DN, with increased risk in carriers of the C allele, including a significant additive per allele effect (OR 1.39, 95% CI 1.10–1.74) and a dominant model effect (OR 1.47, 95% CI 1.11–1.96). In contrast, VEGFA rs2010963 showed no evidence of association across genetic models. Conclusions: In Slovenian patients with T2DM, ANGPT2 rs2442598 is associated with DN, whereas VEGFA rs2010963 is not. This association suggests that ANGPT2 genetic variation may influence DN risk and supports further functional work to define the biological effects of rs2442598. Full article

Diabetic kidney disease (DKD) affects a substantial proportion of individuals with diabetes mellitus and represents the leading cause of end-stage renal disease worldwide. Familial aggregation studies consistently demonstrate that genetic factors contribute significantly to DKD susceptibility beyond metabolic and hemodynamic determinants. The carnosine dipeptidase 1 (CNDP1) gene on chromosome 18q22.3 has emerged as a compelling susceptibility locus, with a trinucleotide (CTG) repeat polymorphism in exon 2 that encodes the Mannheim variant, which has demonstrated protective associations in selected populations. Individuals homozygous for the shorter (CTG)₅ allele exhibit reduced serum carnosinase-1 concentrations and activity, resulting in elevated tissue carnosine levels. Carnosine exerts multiple renoprotective effects, including antioxidant activity, inhibition of advanced glycation end-product formation, and attenuation of profibrotic signaling. Experimental models demonstrate that genetic or pharmacological reduction in carnosinase activity attenuates diabetic kidney injury. Early clinical studies of carnosine supplementation report improvements in albuminuria and oxidative stress markers, though available trials are limited in size, duration, and population scope. Therapeutic targeting of CNDP1 via carnosinase inhibition, therefore, represents a biologically grounded yet still emerging pharmacological strategy. This review synthesizes genetic, molecular, and translational evidence supporting CNDP1 as a model for genetics-informed therapeutic development in DKD, while highlighting important population-specific variation in allele frequencies that constrain universal clinical applicability. Full article

Diabetic kidney disease (DKD) persists as the leading cause of chronic kidney disease (CKD) and often leads to end-stage renal disease (ESRD). Worldwide, 30–50% of patients with diabetes are affected by DKD, while DKD contributes to about half of ESRD. Previously, DKD had been defined based on overt proteinuria—that is, a urine albumin-to-creatinine ratio (UACR) above 300 mg/g—after a stage of microalbuminuria (UACR 30–300 mg/g). However, emerging data suggest that a significant number of patients develop renal functional decline without albuminuria, suggesting that DKD can occur in the absence of protein excretion. This phenotype of normoalbuminuric or non-proteinuric DKD (NA-DKD or NP-DKD) is emerging as an important clinical entity. It is characterized by a gradual decline in renal function, commonly with an annual reduction in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m² or an eGFR < 60 mL/min/1.73 m², while the UACR remains < 30 mg/g. Growing rates of NP-DKD expose limitations inherent in traditional models of DKD pathogenesis and underscore the need for diagnostic and therapeutic paradigms that are not reliant on albuminuria-only criteria. Here, we present a comprehensive review of the NP-DKD to guide a more inclusive model of DKD pathogenesis, its diagnosis, and therapy. Full article

The discovery of apolipoprotein L1 (APOL1) risk polymorphisms has significantly changed our knowledge of kidney disease susceptibility and development in African American populations. Several non-diabetic kidney disorders, such as focal segmental glomerulosclerosis (FSGS), collapsing glomerulopathy, HIV-associated nephropathy (HIVAN), and accelerated chronic kidney disease (CKD) development, are significantly more likely to occur in people with two coding variations, G1 and G2. The significance of context-dependent pathogenic processes is highlighted by the poor penetrance and remarkable phenotypic variety of APOL1-associated kidney disease, despite its substantial impact. This review synthesizes current knowledge of APOL1 biology through a molecular framework, emphasizing gain-of-toxic-function effects of risk variants in podocytes, dysregulated ion fluxes, mitochondrial dysfunction, impaired proteostasis, and activation of innate immune and inflammatory signaling pathways. We describe how the well-recognized “second-hit” paradigm has a biological basis, driven by strong inducibility by interferons and immunological activation, as well as strict basal regulation of APOL1 expression. Lastly, we explore future approaches to precision nephrology and highlight translational advancements, such as APOL1 gene-silencing techniques. This review provides a mechanistic roadmap for translating APOL1 biology into targeted therapeutic strategies by integrating genetics, cell biology, immunology, and systems-level approaches. Full article

The high concentration of the inflammatory cytokine IL-36 in the serum of patients with type 2 diabetes mellitus (T2DM), along with the reduced renal damage observed in IL-36R knockout mice following ischemia–reperfusion-induced acute kidney injury, suggests a significant association between IL-36 activity and diabetic complications such as diabetic nephropathy (DN). It is also known that minor structural alterations in glomerular tissues can lead to changes in blood vessel pressure, potentially contributing to the development of DN, with inflammation acting as a triggering factor. However, further studies are needed to confirm this relationship. In this study, we observed that mesangial (MES-SV40) cells cultured under high-glucose conditions produced IL-36α in a dose-dependent manner. This cytokine production was also detected in mesangial cells from the glomerular tissues of mice with a high-calorie diet-induced T2DM, whereas healthy mice did not show such expression. In addition, we observed that mouse endothelial cells (SVECs) showed increased tubule formation in co-culture with MES-SV40 cells that had been previously exposed to 30 mmol/L glucose, as well as with the supernatant from these cells. IL-36R expression was confirmed in endothelial cells, as well as the angiogenic effect of IL-36α. Given that elevated VEGF levels have been reported in patients with DN by other authors, our results suggest that IL-36 produced by mesangial cells under high-glucose conditions may promote angiogenesis in glomerular tissues, potentially initiating the development of diabetic nephropathy. Full article

Background: In patients with diabetes or hypertension, if appropriate intervention is not initiated early in the course of kidney disease, not only does the risk of progressing to end-stage renal failure increase, but mortality associated with vascular complications also rises as the disease progresses; therefore, there is an urgent need to develop urinary biomarkers that enable early diagnosis and prediction of disease progression. Methods: This two-year prospective observational study involved 185 outpatients. Patients were classified into two groups based on their baseline urinary L-FABP levels relative to the reference value of 8.4 μg/g·Cr at the start of the study. The rate of eGFR decline during the observation period was evaluated. Results: The results showed an interaction (synergistic effect) between urinary L-FABP and time in patients with diabetes or hypertension who had an eGFR of at least 60 mL/min/1.732 m²/kg/1.732 m². Patients with high urinary L-FABP levels (>8.4 μg/g·Cr) exhibited a notably faster eGFR decline compared with those with low levels (≤8.4 μg/g·Cr). This finding suggests the potential of urinary L-FABP as a predictor of renal function decline; we evaluated this utility using the area under the ROC curve (AUC) and logistic regression analysis. The results indicate that urinary L-FABP holds potential as a predictor of renal function decline in diabetic or hypertensive patients with preserved eGFR. Conclusions: Among the analysis groups in which the validation was conducted, it was demonstrated that urinary L-FABP holds potential as a predictor of renal function decline in patients with diabetes or hypertension who have a maintained eGFR. Given that urinary L-FABP is thought to reflect tubulointerstitial damage associated with renal microcirculatory impairment, its future utility as a urinary biomarker for the early diagnosis and prognosis of chronic kidney disease (CKD) is anticipated. Full article

Diabetes is a pivotal risk factor for cardiovascular disease as well as microvascular complications, including retinopathy and nephropathy. Chronic hyperglycemia is a key player in linking diabetes with endothelial dysfunction which, in turn, contributes to cardiovascular disease. Indeed, hyperglycemia acts as a trigger for endothelial dysfunction, promoting a shift in the endothelium from a protective, anti-inflammatory state to a dysfunctional, injury-prone phenotype. A hyperglycemic environment triggers several pathogenetic mechanisms, including alterations in bioenergetics, production of advanced glycation end products, oxidative stress and mitochondrial dysfunction, all contributing to endothelial dysfunction. The activation of these pathophysiological mechanisms by hyperglycemia culminates in reduced nitric oxide production, as well as the induction of oxidative stress and inflammation, all of which are pivotal in impairing endothelial homeostasis and promoting cellular damage. Besides these classical mechanisms, there is growing attention on novel pathogenetic factors linking diabetic hyperglycemia with endothelial dysfunction, such as the ACE2 protein. The latter is emergeing for its potential to counter hyperglycemia-induced cellular damage through its vasoprotective and anti-inflammatory actions, making it a promising therapeutic target for tackling endothelial dysfunction. This review provides an overview of classical as well as emerging mechanisms underpinning the deleterious effects of diabetic hyperglycemia on endothelial dysfunction. In turn, understanding the molecular interconnections between hyperglycemia and endothelial dysfunction is crucial for developing novel strategies to restore endothelial homeostasis and mitigate diabetic vascular complications. Full article