Abstract Background and Aims Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces the expression of genes coding for antioxidant proteins and phase II detoxifying enzymes. Repressor molecule Kelch-like ECH-associated protein 1 (Keap1) and several microRNAs (miRNA) negatively regulate Nrf2 gene expression at post-transcriptional level. Oxidative stress is a major factor for kidney damage in diabetes but the role of Nrf2 in kidney dysfunction in diabetes is still unclear. Method To test whether the gene expression of Nrf-2 is downregulated in type-2 diabetes and whether kidney dysfunction per se further reduces Nrf2 in diabetic patients with diabetic nephropathy, we carried out a case-control study including 99 participants divided into three independent groups: 33 patients with diabetic nephropathy (DN), 33 patients with type 2 diabetes without nephropathy (D) and 33 control subjects (C), all accurately matched for age and sex. Standard ANOVA compared outcome measures in the three groups. Multiple linear regression analysis was used to test the expression levels of Keap1, miR-28-5p, miR-93-5p, miR-30e-5p, miR-125b-5p and miR-150-5p as potential mediators in the observed reduction of Nrf2 mRNA levels in patients with diabetic nephropathy. Results In patients with diabetic nephropathy, Nrf2 gene expression levels (0.82 arbitrary units, AU, IQR: 0.60-1.22 AU) were significantly lower than in diabetic patients without nephropathy (1.19 AU, 0.90-1.38 AU, P = 0.01) and control subjects (0.82 AU, 0.60-1.22 AU vs 1.04 AU, 0.87-1.66, P = 0.02) while there was no difference between diabetic patients without nephropathy and control subjects (P = 0.69). Keap1 gene expression levels were almost identical in patients with and without diabetic nephropathy (1.15 AU, 0.63-2.14 AU vs 1.13 AU, 0.79-1.73 AU, P = 0.91) and higher than in control subjects (1.15 AU, 0.63-2.14 AU vs 0.79 AU, 0.49-1.08 AU, P = 0.046). MiRNA expression levels were comparable in diabetic patients with and without nephropathy, but miRNA 30e-5p was lower in patients with diabetic nephropathy than in diabetic patients without nephropathy (0.91 AU, 0.76-1.10 AU vs 1.06 AU, 0.89-1.23 AU, P = 0.016). The expression levels of Nrf2 and miRNA 30e-5p were unrelated in patients with (r = 0.15, P = 0.44) and without (r = -0.02, P = 0.90) diabetic nephropathy. In linear regression analyses, eGFR emerged as the first factor in rank for explaining the difference in Nrf2 mRNA levels (explained variance 76%) among patients with and without diabetic nephropathy. Conclusion This case-control study comparing the gene expression level of Nrf2 in diabetic patients with and without nephropathy shows that kidney dysfunction is the key factor that explains the variability in Nrf2 mRNA levels in diabetes. These data suggest a primary role of Nrf2 in redox homeostasis and kidney damage in diabetic nephropathy.
Insulin glargine (IG), with its non-peaking action profile, might be useful in diabetic pregnancy. However, data on its safety are limited and its use during pregnancy is not recommended. This study focused on the effects of IG on perinatal outcome, particularly to estimate the rate of congenital anomalies and birthweight.This retrospective study included women with pre-gestational diabetes who used IG before (at least 1 month) and during pregnancy. For all women we recorded data regarding maternal glycaemic control and pregnancy outcome. We also compared women treated with IG throughout pregnancy and women who stopped taking IG at an earlier stage.From 27 centres, 107 Type 1 diabetic pregnancies were identified. IG was started 10.3 +/- 6.9 months before conception and in 57.4% of cases was stopped during the first trimester; 42.6% of women continued using it until the end of pregnancy. There were six abortions (four spontaneous and two induced) and five newborns (4.9%) with congenital anomalies. Glycaemic control, birthweight and the prevalence of macrosomia and neonatal morbidity were similar in women who used IG for the full term compared with those who stopped IG earlier during pregnancy.This study, although limited, suggests that IG is safe and effective; the rate of congenital malformations was within the range expected for diabetic pregnancies treated with more traditional forms of insulin. IG used throughout pregnancy did not seem to influence birthweight or increase adverse outcomes.
The insulin regimen with two daily injections is still that more frequently used. Often regular and NPH insulins are mixed at different ratios according to the patient's need; however, the mixture preparation can involve several errors. Efficacy, safety and compliance were evaluated comparing a premixture 3/7 (Actraphane HM) with extemporary mixtures of regular + NPH at mixing ratios ranging from 2/8 to 4/6, in a cross-over study of 8 weeks involving 20 insulin dependent diabetics. Metabolic control, hypoglycaemic episodes, insulin dose and proportions were similar with both treatments while a higher compliance was achieved with the premixture. In conclusion, premixture 3/7 and extemporary mixture (from 2/8 to 4/6) obtain the same efficacy and safety but the former shows a higher acceptability.
