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Objective: Evidence is limited regarding the associations between vitamin D status and microvascular complications in individuals with type 2 diabetes (T2D), among whom vitamin D deficiency or insufficiency is particularly common. In this study we aimed to prospectively investigate the associations of serum 25-hydroxyvitamin D [25(OH)D] and vitamin D receptor (VDR) polymorphisms with risk of diabetic microvascular complications., Research Design and Methods: This analysis included 14,709 participants with T2D who were free of microvascular complications from the UK Biobank. Incidence of diabetic microvascular complications was ascertained via electronic health records. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs., Results: Median serum 25(OH)D concentration was 40.7 nmol/L (interquartile range 27.5, 56.4). During a median of 11.2 years of follow-up, 1,370 people developed diabetic microvascular complications. Compared with participants with 25(OH)D <25 nmol/L, individuals with 25(OH)D ≥75 nmol/L had a multivariable-adjusted HR of 0.65 (95% CI 0.51, 0.84) for composite diabetic microvascular complications, 0.62 (0.40, 0.95) for diabetic retinopathy, 0.56 (0.40, 0.79) for diabetic nephropathy, and 0.48 (0.26, 0.89) for diabetic neuropathy. In addition, in comparisons with participants with 25(OH)D <25 nmol/L and minor allele homozygotes (TT of rs1544410 and GG of rs731236), the multivariable-adjusted HRs of composite diabetic microvascular complications were 0.54 (0.38, 0.78) and 0.55 (0.38, 0.80) for participants with serum 25(OH)D ≥50 nmol/L and major allele homozygotes (CC and AA), respectively, although no significant interaction was observed., Conclusions: Higher serum 25(OH)D concentrations were significantly associated with lower risk of diabetic microvascular complications, including diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Our findings suggest a potential beneficial role of maintaining adequate vitamin D status in the prevention of diabetic microvascular complications., (© 2023 by the American Diabetes Association.)

Background: The influence of overall lifestyle behaviors on diabetic microvascular complications remains unknown. In addition, the potential mediating biomarkers underlying the association is unclear. This study aimed to examine the associations of the combined lifestyle factors with risks of total and individual microvascular complications among patients with type 2 diabetes (T2D) and to explore the potential mediation effects of metabolic biomarkers., Methods and Findings: This retrospective cohort study included 15,104 patients with T2D free of macro- and microvascular complications at baseline (2006 to 2010) from the UK Biobank. Healthy lifestyle behaviors included noncurrent smoking, recommended waist circumference, regular physical activity, healthy diet, and moderate alcohol drinking. Outcomes were ascertained using electronic health records. Over a median of 8.1 years of follow-up, 1,296 cases of the composite microvascular complications occurred, including 558 diabetic retinopathy, 625 diabetic kidney disease, and 315 diabetic neuropathy, with some patients having 2 or 3 microvascular complications simultaneously. After multivariable adjustment for sociodemographic characteristics, history of hypertension, glycemic control, and medication histories, the hazard ratios (95% confidence intervals (CIs)) for the participants adhering 4 to 5 low-risk lifestyle behaviors versus 0 to 1 were 0.65 (0.46, 0.91) for diabetic retinopathy, 0.43 (0.30, 0.61) for diabetic kidney disease, 0.46 (0.29, 0.74) for diabetic neuropathy, and 0.54 (0.43, 0.68) for the composite outcome (all Ps-trend ≤0.01). Further, the population-attributable fraction (95% CIs) of diabetic microvascular complications for poor adherence to the overall healthy lifestyle (<4 low-risk factors) ranged from 25.3% (10.0%, 39.4%) to 39.0% (17.7%, 56.8%). In addition, albumin, HDL-C, triglycerides, apolipoprotein A, C-reactive protein, and HbA1c collectively explained 23.20% (12.70%, 38.50%) of the associations between overall lifestyle behaviors and total diabetic microvascular complications. The key limitation of the current analysis was the potential underreporting of microvascular complications because the cases were identified via electronic health records., Conclusions: Adherence to overall healthy lifestyle behaviors was associated with a significantly lower risk of microvascular complications in patients with T2D, and the favorable associations were partially mediated through improving biomarkers of glycemic control, systemic inflammation, liver function, and lipid profile., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Geng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Increased oxidative stress and activation of protein kinase C (PKC) under hyperglycemia have been implicated in the development of diabetic nephropathy. Because reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NOX1 accelerate the translocation of PKC isoforms, NOX1 is postulated to play a causative role in the development of diabetic nephropathy. Hyperglycemia was induced in wild-type and Nox1-deficient mice (KO) by two doses of streptozotocin injection. At 3 weeks after the induction of hyperglycemia, glomeruli and cortical tubules were isolated from kidneys. The mRNA level of Nox1 was significantly upregulated in the renal cortex at 3 weeks of hyperglycemia. Urinary albumin and expression of inflammatory or fibrotic mediators were similarly elevated in diabetic wild-type and KO; however, increases in glomerular volume and mesangial matrix area were attenuated in diabetic KO. Nox1 deficiency significantly reduced the levels of renal thiobarbituric acid-reacting substances and 8-hydroxydeoxyguanosine, membranous translocation of PKCα/β, activity of PKC, and phosphorylation of p38 mitogen-activated protein kinase in the diabetic kidney. Furthermore, increased staining of senescence-associated β-galactosidase in glomeruli and cortical tubules of diabetic mice was significantly suppressed in KO. Whereas the levels of cyclin-dependent kinase inhibitors, p16(INK4A) and p21(Cip1), were equivalent between the genotypes, increased levels of p27(Kip1) and γ-H2AX, a biomarker for DNA double-strand breaks, were significantly attenuated in isolated glomeruli and cortical tubules of diabetic KO. Taken together, NOX1 modulates the p38/p27(Kip1) signaling pathway by activating PKC and promotes premature senescence in early stage diabetic nephropathy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Compelling evidence has demonstrated that arsenic (As) exposure is associated with kidney injuries. Given that inflammatory responses and immune imbalances are the root causes of several kidney diseases, this study investigated the potential mechanisms underlying NLRP3 inflammasome activation in As-induced kidney injury. A rat model of sub-chronic As exposure was established via oral administration of NaAsO2. The results revealed that urinary β-2-microglobulin (β2-MG), N-acetyl-β-D-glucosidase (NAG) and albumin (ALB) were increased in the As-exposed group, reflecting kidney impairment. Moreover, significant glomerular vacuole-like changes, tubular dilatation and inflammatory cell infiltration were observed. Meanwhile, the expression levels of neutrophil gelatinase-associated lipocalin (NGAL), IL-1β and IL-18 were enhanced in the kidney tissues of As-treated rats. Further, increased expression of NLRP3, ASC and caspase-1, which are NLRP3 inflammasome-associated proteins, were observed in the kidney tissues of rats in the As-treated groups. The expression levels of the NLRP3 upstream regulators C/EBPβ and TFAM were also elevated. These findings suggest that sub-chronic As exposure triggers inflammatory responses in rat kidney tissue and impairs kidney function. The underlying mechanisms may be related to the C/EBPβ–TFAM pathway and activation of the NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]