People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.

Background: Recently deorphanized G protein-coupled receptor 146 (GPR146) was shown to respond to signal from a newly identified hormone—cholesin—and to play a role in hepatic lipid metabolism. However, the importance of its biological activity in human organism remains elusive, mainly due to the lack of studies on human tissues up to this point. This study aimed to identify the cholesin receptor-associated genes and clinical factors linked with their expression in cardiovascular system and associated adipose tissues. Methods: Right cardiac auricle, aortic wall, saphenous vein, and adipose tissue (periaortic-PAT, epicardial-EAT, thymic-TAT) samples were collected during coronary artery bypass grafting. Clinical records of the study participants were assessed for the presence of diabetes, medications taken and serum cholesterol levels. GPR146 mRNA expression in all gathered tissues was assessed with qPCR, and RNA seqencing was performed in selected tissues of 20 individuals to identify pathways associated with GPR146 expression. Results: We included 46 participants [37 male, 23 with type 2 diabetes, median age 68.50 (Q1–Q3: 63.00–72.00) years, BMI 28.39 (26.06–31.49) kg/m²]. GPR146 expression in adipose tissues significantly correlated with BMI, c-peptide, total cholesterol, and LDL concentrations. Selected metabolic pathways were significantly and positively enriched in GPR146-dependent manner. GPR146-coexpressed genes contained key regulators of lipid metabolism involved in such pathways as fatty acid metabolism, tricarboxilic acid cycle and peroxisomal metabolism. Those genes correlated positively with serum concentrations of LDL, HDL, and total cholesterol. SGLT2i treatment was associated with inversion of GPR146-related signature in EAT, suggesting potential impact on cholesin-GPR146 network. Conclusions: GPR146 expression is associated with serum lipids and metabolically-relevant transcriptomic changes in EAT similar to SGLT2i-associated ones. Graphical

Introduction: To determine the impact of single nucleotide polymorphisms (SNPs) in MTHFR and MTRR genes on disease activity and the presence of MTX therapy adverse events in Polish children with juvenile idiopathic arthritis (JIA). Methods: SNP genotyping was performed using genomic DNA isolated from peripheral blood samples. Results: Patients with MTHFR rs1801133 CT/TT variant had higher values of inflammatory markers, number of joints with active arthritis, and JADAS-71 value at the baseline of MTX treatment. Children with MTRR rs1801394 AG/AA variant presented higher inflammatory marker values at JIA diagnosis. Conclusions: MTHFR rs1801133 and MTRR rs1801394 polymorphisms are associated with higher disease activity at the moment of JIA diagnosis.

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. It is believed that children with JIA have lower cardiopulmonary capacity and worse exercise tolerance. The gold standard for assessing physical fitness is aerobic fitness, commonly referred to as the maximum or peak oxygen uptake volume (peakVO₂) measured during a maximum load exercise test. Reduced aerobic fitness may play a key role in predicting the health of JIA patients as it has been associated with cardiovascular diseases and increased adult mortality. Methods: The aim of this study was to assess the oxygen capacity of adolescents with JIA along with other cardiopulmonary parameters in order to determine a group of patients with increased risk of developing cardiovascular diseases in comparison with healthy individuals. Patients were assessed based on parameters such as age, sex, type of JIA, laboratory parameters, physical activity, and treatment. Results: Patients with JIA had lower median values of peakVO₂ (29.05 vs. 38.02 mL/min/kg, p < 0.001), as well as other crucial cardiopulmonary parameters, such as O₂ pulse, minute ventilation, oxygen uptake efficiency slope, and cardiac output than in the healthy control group. The ventilatory anaerobic threshold was achieved earlier and at lower VO₂ values in children with JIA (p = 0.0001). Children with JIA also had lowered respiratory parameters such as maximal voluntary ventilation (p = 0.0031) and tidal volume (p = 0.0002). Patients who were physically active (moderate-intensity physical activity lasting at least 60 min per day) had significantly higher peakVO₂ (p = 0.0099) and ΔVO₂/ΔWR relationship (p = 0.0041) values than JIA patients who were not physically active. Conclusions: Children with JIA show moderate to severe physical impairment. Reduced physical fitness and a low level of activity might be associated with further deterioration of patient’s condition, which might contribute to increased risk of cardiovascular disease, social exclusion and deterioration of quality of life in this group of patients. Exercise programs that improve aerobic fitness and increase muscle strength should be individualized and modified based on the individual needs and capabilities of the patient.