Diabetes leads to reduced nitric oxide bioavailability, resulting in endothelial dysfunction. However, overproduction of nitric oxide due to hyperglycaemia is associated with oxidative stress and tissue damage. The objective of this study was to characterise nitric oxide production (NO) and added nitrite and nitrate (NO2‑+NO3‑) concentration in the blood and urine of patients with and without diabetic nephropathy. A total of 268 patients with type 1 diabetes and 69 healthy subjects were included. Diabetic nephropathy was defined as macroalbuminuria and/or estimated glomerular filtration rate below 60 ml/min/1.73 cm2. NO2‑+NO3‑ concentration was measured by Griess reaction. Production of NO was detected by electron paramagnetic resonance spectroscopy. Blood NO was demonstrated to be higher (P<0.001) and serum NO2‑+NO3‑ was lower (P=0.003) in patients with type 1 diabetes and no nephropathy vs. healthy subjects. However, serum NO2‑+NO3‑ concentration in patients with diabetes and nephropathy did not differ from the levels observed in healthy controls. Urine excretion of NO2‑+NO3‑ was significantly decreased in patients with nephropathy, compared with patients without diabetic kidney disease (P=0.006) and healthy subjects (P=0.010). A significant positive correlation was observed between urine NO2‑+NO3‑ and estimated glomerular filtration rate in patients with type 1 diabetes (P=0.002) and healthy subjects (P=0.008). Estimated glomerular filtration rate, albuminuria and diabetic nephropathy status were significant predictors of the whole blood NO and NO2‑+NO3‑ in serum and urine in patients with type 1 diabetes, as identified by linear regression models. The present study concludes that NO metabolism is impaired by type 1 diabetes and diabetic nephropathy.

The association of endotoxemia with metabolic syndrome (MS) and low-grade inflammation in type 1 diabetes (T1D) is little-studied. We investigated the levels of lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP), endogenous anti-endotoxin core antibodies (EndoCAb IgG and IgM) and high-sensitivity C-reactive protein (hsCRP) in 74 T1D patients with different MS statuses and 33 control subjects. Within the T1D group, 31 patients had MS. These subjects had higher levels of LPS compared to patients without MS (MS 0.42 (0.35–0.56) or no MS 0.34 (0.3–0.4), p = 0.009). MS was associated with LPS/HDL (OR = 6.5 (2.1; 20.0), p = 0.036) and EndoCAb IgM (OR = 0.32 (0.11; 0.93), p = 0.036) in patients with T1D. LBP (β = 0.30 (0.09; 0.51), p = 0.005), EndoCAb IgG (β = 0.29 (0.07; 0.51), p = 0.008) and the LPS/HDL ratio (β = 0.19 (0.03; 0.41, p = 0.084) were significantly associated with log-transformed hsCRP in T1D. Higher levels of hsCRP and EndoCAb IgG were observed in T1D compared to the control (p = 0.002 and p = 0.091, respectively). In contrast to the situation in the control group, LPS did not correlate with LBP, EndoCAb, leukocytes or HDL in T1D. To conclude, endotoxemia is associated with low-grade inflammation, MS and a distinct response to LPS in T1D.

The aim of the study was to compare telomere lengths and circulating proteasome concentrations in patients with different stages of diabetic retinopathy and type 1 diabetes in Latvia and Lithuania. Methods. Patients with no diabetic retinopathy and with non-proliferative diabetic retinopathy were included in the NDR/NPDR group (n = 187). Patients with proliferative diabetic retinopathy and status post laser-photocoagulation were included int the PDR/LPC group (n = 119). Telomeres were evaluated by real-time quantitative polymerase chain reaction. Proteasome concentration was measured by ELISA. Results. Telomeres were longer in PDR/LPC (ΔCT 0.21 (0.12–0.28)) vs. NDR/NPDR (ΔCT 0.18 (0.1–0.28)), p = 0.036. In NDR/NPDR, telomeres were correlated negatively with age (R = −0.17, p = 0.019), BMI (R = −0.21, p = 0.004), waist/hip ratio (R = −0.21, p = 0.005), total cholesterol (R = −0.18, p = 0.021), and low-density cholesterol (R = −0.20, p = 0.010), and positively with estimated glomerular filtration rate (eGFR) (R = 0.28, p < 0.001). None of the above correlations were observed in PRD/LPC. Proteasome concentrations were lower in PDR/LPC (130 (90–210) ng/mL) vs. NDR/NPDR (150 (100–240) ng/mL), p = 0.024. This correlated negatively with eGFR (R = −0.17, p = 0.025) in the NDR/NPDR group and positively with age (R = 0.23, p = 0.014) and systolic blood pressure (R = 0.20, p = 0.032) in the PRD/LPC group. Telomere lengths did not correlate with proteasome concentrations. Conclusion. Longer telomeres and lower circulating proteasome concentrations are observed in patients with type 1 diabetes and advanced diabetic retinopathy.

We explored differences in the DNA methylation statuses of PSMA6, PSMB5, HIF1A, and KEAP1 gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR) stages. Study subjects included individuals with no DR (NDR, n = 41), those with non-proliferative DR (NPDR, n = 27), and individuals with proliferative DR or those who underwent laser photocoagulation (PDR/LPC, n = 46). DNA methylation was determined by Zymo OneStep qMethyl technique. The methylation of PSMA6 (NDR 5.9 (3.9–8.7) %, NPDR 4.5 (3.8–5.7) %, PDR/LPC 6.6 (4.7–10.7) %, p = 0.003) and PSMB5 (NDR 2.2 (1.9–3.7) %, NPDR 2.2 (1.9–3.0) %, PDR/LPC 3.2 (2.5–7.1) %, p < 0.01) differed across the groups. Consistent correlations were observed between the methylation levels of HIF1A and PSMA6 in all study groups. DNA methylation levels of PSMA6, PSMB5, and HIF1A genes were positively correlated with the duration of diabetes, HbA1c, and albuminuria in certain study groups. Univariate regression models revealed a significant association between the methylation level z-scores of PSMA6, PSMB5, and HIF1A and severe DR (PSMA6: OR = 1.96 (1.15; 3.33), p = 0.013; PSMB5: OR = 1.90 (1.14; 3.16), p = 0.013; HIF1A: OR = 3.19 (1.26; 8.06), p = 0.014). PSMB5 remained significantly associated with DR in multivariate analysis. Our findings suggest significant associations between the severity of DR and the DNA methylation levels of the genes PSMA6, PSMB5, and HIF1A, but not KEAP1 gene.

Background: Serum C-reactive protein (CRP) levels vary depending on radiological and bacteriological findings at the time of tuberculosis (TB) diagnosis. However, the utility of this biomarker in monitoring response to anti-TB treatment and identifying patients at risk of treatment failure is not well established. Objectives: This study evaluated the impact of patients’ baseline characteristics and anti-TB drug plasma exposure on the early reduction in serum CRP levels and its relationship with treatment response. Methods: We enrolled 42 patients with drug-susceptible pulmonary TB, who received a standard six-month regimen. The plasma concentrations of four anti-TB drugs were analysed using LC-MS/MS. Clinically relevant data, including serum CRP levels before and 10–12 days after treatment initiation (CRP_10–12d), were obtained from electronic medical records and patient questionnaires. Results: In 10–12 days, the median serum CRP level decreased from 21.9 to 6.4 mg/L. Lower body mass index, positive sputum-smear microscopy results, and lung cavitations at diagnosis were related to higher biomarker levels at both time points; smoking had a more pronounced effect on serum CRP_10–12d levels. Variability in anti-TB drug plasma exposure did not significantly affect the reduction in serum CRP levels. The serum CRP_10–12d levels, or fold change from the baseline, did not predict the time to sputum culture conversion. Conclusions: Disease severity and patient characteristics may influence the pattern of early CRP reduction, while anti-TB drug plasma exposure had no significant effect at this stage. These early changes in serum CRP levels were not a predictor of response to anti-TB therapy.

Aims: Continuous glucose monitoring (CGM) enables scalable digital phenotyping by capturing detailed daily glucose profiles and has been shown to improve glycaemic control in individuals with type 1 diabetes (T1D). We hypothesized that clustering CGM-derived metrics could identify distinct glycemic phenotypes associated with increased insulin resistance, systemic inflammation, and risk of metabolic derangements, with potential implications for optimization of clinical care. Materials and methods: This cross-sectional study applied a hierarchical clustering approach to stratify 75 individuals with T1D based on CGM metrics obtained over 14 days (Libre ProIQ). Clustering was performed using Ward’s minimum variance linkage and Euclidean distance on six CGM metrics (average glucose, coefficient of variance, time above range, time below range, time in range, and frequency of low glucose events). The resulting groups, poorly controlled diabetes (PCD) and moderately controlled diabetes (MCD), were compared for insulin resistance markers (estimated glucose disposal rate, eGDR), metabolic dysfunction-associated steatotic liver disease (MASLD) risk markers (fatty liver index, FLI; hepatic steatosis index, HSI), and inflammation and endotoxaemia markers. Results: Compared to MCD, subjects in the PCD group had significantly higher insulin resistance (eGDR: 4.4 vs. 7.3 mg/kg/min, p = 0.001), elevated liver enzymes (ALT: 26 vs. 20 U/L, p = 0.005; AST: 28 vs. 23 U/L, p = 0.049), increased MASLD risk markers (HSI: 37 vs. 35, p = 0.033; FLI: 29 vs. 17, p = 0.034), and higher systemic inflammation (CRP: 1.82 vs. 0.81 mg/L, p = 0.020; lipopolysaccharide-binding protein (LBP): 11.7 vs. 8.4 EU/mL, p = 0.024). Time above range correlated positively with liver and inflammatory markers, while time in range correlated negatively. Mediation analysis suggested that FLI partially mediated the effect of poor glycemic control on inflammation. Conclusions: In this cross-sectional cohort of adults with T1D, poorer CGM-derived glycaemic control was associated with higher systemic inflammation and higher surrogate-marker-defined MASLD risk.