Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents “mandatory damage” in the development of microvascular complications and only “introductory damage” in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies.

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate–calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.

Osteoglycin (OGN) could be a biomarker of mild kidney function impairment in type 2 diabetes (T2D). Our study aimed to determine the association between serum OGN and impaired kidney function risk in T2D patients and to analyze its potential role as an estimator of kidney disturbances in this population. This cross-sectional study included 147 T2D patients (65 ± 8 years, 58.5% males), and 75 healthy controls (63 ± 10 years, 36% males). Circulating OGN levels were determined by ELISA. Linear regression modeling was performed to determine the variables influencing circulating OGN, and an ROC curve was plotted to assess the usefulness of OGN as an estimator of diabetic kidney disease risk. Circulating OGN was significantly increased in T2D patients compared to controls (18.41 (14.45–23.27) ng/mL vs. 8.74 (7.03–12.35) ng/mL; p < 0.001). We found a progressive increase in serum OGN according to the severity of kidney impairment in T2D patients (normal kidney function: 16.14 (12.13–20.48) ng/mL; mildly impaired kidney function: 19.15 (15.78–25.90) ng/mL; moderate impaired kidney function: 21.80 (15.06–29.22) ng/mL; p = 0.006). Circulating OGN was an independent estimator of mildly impaired kidney function risk in T2D patients. We suggest that serum OGN could act as an albuminuria-independent biomarker of incipient kidney dysfunction in T2D patients.

Non-alcoholic fatty liver disease (NAFLD) seems to have some molecular links with atherosclerosis (ATH); however, the molecular pathways which connect both pathologies remain unexplored to date. The identification of common factors is of great interest to explore some therapeutic strategies to improve the outcomes for those affected patients. Differentially expressed genes (DEGs) for NAFLD and ATH were extracted from the GSE89632 and GSE100927 datasets, and common up- and downregulated DEGs were identified. Subsequently, a protein–protein interaction (PPI) network based on the common DEGs was performed. Functional modules were identified, and the hub genes were extracted. Then, a Gene Ontology (GO) and pathway analysis of common DEGs was performed. DEGs analysis in NAFLD and ATH showed 21 genes that were regulated similarly in both pathologies. The common DEGs with high centrality scores were ADAMTS1 and CEBPA which appeared to be down- and up-regulated in both disorders, respectively. For the analysis of functional modules, two modules were identified. The first one was oriented to post-translational protein modification, where ADAMTS1 and ADAMTS4 were identified, and the second one mainly related to the immune response, where CSF3 was identified. These factors could be key proteins with an important role in the NAFLD/ATH axis.

PARP-1 has been linked to the progression of several types of cancer. We have recently reported that PARP-1 influences tumor progression in CRC through the regulation of CSCs in a p53-dependent manner. In this study, we propose that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) could act as a mediator. We evaluated the expression of iNOS in a cohort of patients previously used to analyze the effects of PARP-1 on CRC in relation to p53 status. We also developed an in vitro model in which PARP-1 was stably overexpressed. In CRC patients, iNOS expression correlated with the differentiation grade, and with a high expression of CSC markers, although only in wild-type p53 tumors, as previously found for PARP-1. In vitro, overexpression of PARP-1 induced increased growth and stemness in wild-type p53 cells, while exerting the opposite effect on mutated ones, as expected. Treatment with 1400 W, a selective inhibitor of iNOS, or gene silencing of the gene counteracted the effects of PARP-1 in both p53 wild-type and p53 mutated cells. Given that the development of resistance has been demonstrated after treatment with PARP-1 inhibitors, iNOS could be considered a new therapeutic target in CRC, although only in patients with wild-type p53 tumors.

Alkaline phosphatase (ALP) deficiency has been linked to reduced physical performance, as seen in hypophosphatasia (HPP). However, its potential role in muscle function has not been fully explored. This was a cross-sectional study in 34 HPP adults and 34 matched healthy controls. Muscle strength was assessed using handgrip strength (HGS), considering values below the 10th percentile of the Spanish population as low strength. Muscle mass was evaluated using dual-energy X-ray absorptiometry and morphometric ultrasound. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and total hip. The prevalence of low muscle strength was significantly higher in the HPP group compared to controls (30% vs. 6%; p = 0.009), with decreased HGS in the HPP group (p = 0.039). Positive associations were observed between ALP and femoral neck BMD, leg circumference, and fat-free mass and an inverse association with tricipital skinfold. Subjects with serum ALP activity below the sex-adjusted median had a significantly higher risk of low muscle strength independently of HPP diagnosis. ALP remained independently associated with HGS (p = 0.005), and a predictive model using ALP values showed strong capability to predict low-muscle-strength risk. Based on these results, we conclude circulating ALP levels are independently associated with muscle strength and may represent a useful biomarker for the early detection of muscle dysfunction. Future longitudinal or interventional studies are needed to assess whether ALP plays a causal role in muscle strength.