Cristian Serafinceanu

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Prevalence of diabetes mellitus and prediabetes in the adult Romanian population: PREDATORR study†

The PREDATORR (PREvalence of DiAbeTes mellitus, prediabetes, overweight, Obesity, dyslipidemia, hyperuricemia and chronic kidney disease in Romania) study is the first national study analyzing the prevalence of diabetes mellitus (DM) and prediabetes, and their association with cardiometabolic, sociodemographic, and lifestyle risk factors in the Romanian population aged 20–79 years.

Metabolic syndrome, adiponectin and proinflammatory status in patients with type 1 diabetes mellitus

Objectives To assess the prevalence of metabolic syndrome and evaluate proinflammatory status in patients with type 1 diabetes, and to analyse the relationship between inflammation, metabolic control and insulin resistance in these patients. Methods Patients with type 1 diabetes were stratified according to the presence or absence of metabolic syndrome. Serum adiponectin, leptin, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and high-sensitivity C-reactive protein (hsCRP) were quantified. Results The prevalence of metabolic syndrome was 28.6% (22/77). Patients with metabolic syndrome had lower adiponectin concentrations and higher leptin, TNF-α, IL-6 and hsCRP concentrations compared with patients without metabolic syndrome. In addition, metabolic syndrome was associated with higher glycosylated haemoglobin and insulin dose, and increased insulin resistance. Conclusions The proinflammatory state associated with metabolic syndrome in patients with type 1 diabetes leads to deterioration of glycaemic control and an increase in the required daily dose of insulin. Early and proactive diagnosis of metabolic syndrome in these patients will allow medication and lifestyle optimization, in order to prevent the occurrence of diabetes complications and improve health-related quality-of-life.

L-arginine catabolism is driven mainly towards nitric oxide synthesis in the erythrocytes of patients with type 2 diabetes at first clinical onset

Background We investigated the l-arginine (l-Arg)–nitric oxide (NO) metabolic pathway in the erythrocytes (RBCs) and plasma of subjects with type 2 diabetes at first clinical onset. Methods RBCs and plasma were collected from 26 patients with type 2 diabetes at first clinical onset and 19 age-matched non-diabetes subjects as controls. l-Arg content was assayed by capillary electrophoresis. We measured arginase activity and nitrate/nitrite concentrations by spectrophotometry, and glycosylated haemoglobin (HbA1c) by standardized immunoturbidimetry. Results We found that, when compared with controls, l-Arg content was similar in RBCs while decreased in the plasma of patients with type 2 diabetes. Interestingly, arginase activity was lower in RBCs and increased in plasma of patients with diabetes. NO production was higher in RBCs in patients with type 2 diabetes, while no difference was found in the plasma of our subjects. Conclusions l-Arg catabolism is driven mainly towards NO synthesis in RBCs of patients with type 2 diabetes at first clinical onset. The decreased RBC arginase activity could be considered a potential mechanism of increased RBC NO production in early diabetes. Therefore, the RBC pool would represent a potentially compensatory intravascular compartment for endothelial dysfunction in diabetes.

The insulin polymorphism -23Hph increases the risk for type 1 diabetes mellitus in the Romanian population

The insulin -23Hph and IGF2 Apa polymorphisms were genotyped in Romanian patients with T1DM (n = 204), T2DM (n = 215) or obesity (n = 200) and normoponderal healthy subjects (n = 750). The genotypes of both polymorphisms were distributed in concordance with Hardy-Weinberg equilibrium in all groups. The -23Hph AA genotype increased the risk for T1DM (OR: 3.22, 95%CI: 2.09-4.98, p < 0,0001), especially in patients without macroalbuminuria (OR: 4.32, 95%CI: 2.54-7.45, p < 0,0001). No other significant association between the alleles or genotypes of insulin -23Hph and IGF2 Apa and diabetes or obesity was identified.

Paraoxonase lactonase activity, inflammation and antioxidant status in plasma of patients with type 1 diabetes mellitus

Objectives To investigate paraoxonase-1 (PON1) lactonase activity, myeloperoxidase (MPO) activity (as a marker of inflammation) and antioxidant status in plasma of patients with type 1 diabetes mellitus. Methods Whole blood and plasma samples were collected from patients with diabetes and healthy control subjects. PON1 lactonase and MPO activities and total antioxidant capacity (TEAC) were determined in plasma. Glycosylated haemoglobin (HbA1c) was quantified in whole blood. Results Plasma PON1 lactonase and MPO activities were significantly higher and TEAC was significantly lower in patients with diabetes (n = 18) compared with healthy control subjects (n = 20). There were significant positive correlations between PON1 lactonase activity and MPO activity and HbA1c level, and plasma MPO and HbA1c. There were significant negative correlations between PON1 lactonase activity and TEAC, and MPO activity and TEAC. Conclusions Increased lactonase activity may inefficiently compensate for the high level of chronic inflammation and low antioxidant capacity in the plasma of patients with type 1 diabetes mellitus.

Potential association of obesity with IL6 G-174C polymorphism and TTV infections

Polymorphisms in IL6, ACE and ATR genes are associated with obesity. Torque Teno virus (TTV) seems to be able to interfere with production of some proinflammatory cytokines associated with obesity and related phenotypes. The aim of this study was to test the potential association between obesity, TTV infection and the IL6 G-174C (rs1800795), ACE I/D (rs4646994), AT1R A1166C (rs5186) polymorphisms. The polymorphisms and the presence of TTV were detected in blood samples from 150 obese and 150 normal-weight, healthy subjects using PCR based methods. IL6-174 CC genotype was more frequent in all obese patients (P=0.02) and in patients without TTV infections (P=0.03) than in controls. Obese women had more frequent TTV infections compared with normal-weight women (P=0.046). Obese subjects, regardless of gender (women P=0.03, men P=0.04), and healthy normal-weight men (P<0.01) carriers of AT1R C allele had higher triglycerides levels compared with non-carriers. The frequency of TTV in the control group (70.67%) was similar to data reported in other populations. The present study indicated that IL6-174 CC genotype and TTV infections in women could be associated with the common form of obesity.

The Influence of Weight Loss on Arterial Stiffness in Obese and Overweight Subjects

Abstract Objectives: The Metabolic Syndrome (MetS) and obesity are among the proven causes of vascular dysfunction. The cardio-ankle vascular index (CAVI) was developed as a method to assess arterial stiffness. The aim of the study was to establish the influence of weight loss on arterial stiffness parameters. Material and Methods: 135 subjects completed a 6 months standardized life style intervention study. Average initial weight was 96.63kg with a BMI of 34.34kg/m2. CAVI and the ankle-brachial index (ABI) were measured and body composition was assessed. Some biochemical markers were also determined. Results: The average weight decreased to 84.61kg, with fat mass loss of 9.6 kg. Mean CAVI decreased from 7.92±1.28 to 7.21±1.08. The decrease in CAVI correlates with the total weight and fat loss rather than the speed of weight loss. Conclusions: Our results show that weight loss can influence arterial stiffness, mainly by decreasing fat tissue mass.

Associations of smoking with cardiometabolic profile and renal function in a Romanian population-based sample from the PREDATORR cross-sectional study

Abstract Background: The impact of smoking on morbidity is well known, but in Romania, limited data are available regarding the smoking prevalence and relationship with cardiometabolic profile and kidney function. Objectives: To assess the association of smoking with cardiometabolic traits and kidney function, in a Romanian population-based sample from the PREDATORR study. Methods: PREDATORR was an epidemiological cross-sectional study. Between 2012 and 2014, participants were randomly selected from the lists of general practitioners and enrolled if they were aged 20 to 79 years, born and living in the past 10 years in Romania. Sociodemographic and lifestyle characteristics were collected through interviewer-administered questionnaires. Results: Overall, 2704 participants were included in the analysis, 18% of them being current smokers and 30.8% former smokers. Current smokers compared to non-smokers had higher total cholesterol (220.6 ± 50.4 versus 213.9 ± 86.8 mg/dl, P = 0.017), LDL-cholesterol (137.8 ± 45.2 versus 130.7 ± 83.7 mg/dl, P = 0.004) and glomerular filtration rate (96.9 ± 16.8 versus 90.7 ± 19.1 ml/min/1.73 m2, P <0.001) in women and higher triglycerides (170.7 ± 129.8 versus 144.3 ± 94.2 mg/dl, P = 0.007), glomerular filtration rate (97.6 ± 17 versus 90.3 ± 18 ml/min/1.73 m2, P < 0.001) and lower HDL-cholesterol (48 ± 15.5 versus 50.4 ± 14.1 mg/dl, P = 0.002) in men. Active smoking was associated with hypercholesterolaemia [OR: 1.40 (95% CI: 1.01–1.96), P = 0.04] and low HDL-cholesterolaemia [OR: 1.39 (95% CI: 1.01–1.91), P = 0.04] and negatively associated with overweight/obesity [OR: 0.67 (95% CI: 0.48–0.94), P = 0.02]. Male former smokers had higher prevalence of abdominal obesity (82.4% versus 76.4%, P = 0.02), hypertriglyceridaemia (43.6% versus 35.6%, P = 0.01), hypertension (64% versus 56.4%, P = 0.01) and ischaemic vascular disease (40.5% versus 30.9%, P = 0.003) than male non-smokers. Conclusion: The PREDATORR study showed a high prevalence of smoking in the adult Romanian population providing data on the association of smoking with cardiometabolic traits.

The Emerging Role of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes. Focus on Dapagliflozin

Abstract Type 2 diabetes is a progressive metabolic disorder, accounting for more than 90% of all cases of diabetes. Treatment strategies target blood glucose reduction and non-glycemic effects that can reduce long-term complications, such as cardiovascular disease. Although metformin is often initially effective as monotherapy, the progressive nature of diabetes frequently requires additional therapies. Sodium-glucose transporter 2 (SGLT2) became a very attractive therapeutic target in diabetes management. The mechanism of action of SGLT2 inhibitors is not dependent on insulin, thus making them attractive options anytime over the course of the disease. Dapagliflozin is a stable and highly selective inhibitor of SGLT2. The reductions in fasting plasma glucose concentration and bodyweight recorded during the first week of treatment in the dapagliflozin groups continued over weeks and years of treatment. Early weight loss with dapagliflozin might be partly due to a mild osmotic diuresis, while the gradual progressive reduction in bodyweight is consistent with a reduction of fat mass. Although dapagliflozin is well tolerated, signs and symptoms suggestive for urinary and/or genital infections were reported during clinical trials in more patients assigned to the drug than in placebo groups.