Kathryna Fontana Rodrigues

The Role of Transforming Growth Factor-Beta in Diabetic Nephropathy

Several studies have demonstrated that chronic and low-grade inflammation is closely linked to type 2 diabetes mellitus. The associated mechanisms are related to synthesis and release of proinflammatory and anti-inflammatory cytokines, mainly by the adipose tissue. Moreover, there are evidences that cytokines and adhesion molecules are important for development of diabetic nephropathy. Among the cytokines associated with inflammatory responses in type 2 diabetes mellitus, the transforming growth factor-β (TGF-β) has been recognized as a central player in the diabetic nephropathy being involved in the development of glomerulosclerosis and interstitial fibrosis, as observed in the course of end-stage renal disease. Although TGF-β1 is classically an anti-inflammatory immune mediator it has been shown that in the presence of IL-6, which increases before the onset of T2D, TGF-β1 favors the differentiation of T helper 17 (Th17) cells that are activated in many pro-inflammatory conditions. Since TGF-β1 mRNA and consequently serum TGF-β1 levels are under genetic control, this review aims to discuss the relationship of TGF-β1 levels and polymorphisms in the development of nephropathy in type 2 diabetes mellitus.

Endocan: a new biomarker associated with inflammation in type 2 diabetes mellitus?

Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

The polymorphism -1131T>C in apolipoprotein A5 gene is associated with dyslipidemia in Brazilian subjects.

BACKGROUND Polymorphisms in apolipoprotein A5 gene (APOA5) have been associated with higher triglyceride levels in many populations. The aim of the study was to determine the allelic and genotypic distribution of the APOA5 -1131T>C polymorphism and to identify the association of the genetic variant and the risk for dyslipidemia. METHODS We genotyped 109 dyslipidemic subjects and 107 controls. The total cholesterol, triglycerides and HDL-c were determined enzymatically. Comparison of means among groups was calculated by ANOVA. Significant differences among groups were evaluated by Student-Newman-Keuls test. RESULTS The minor allele C was more frequent in dyslipidemic subjects than controls (p=0.019) and confers an increased individual risk for dyslipidemia (OR=1.726, CI 95%=1.095-2.721). The genotype analysis by gender showed that this allele was more frequent in dyslipidemic males (p=0.037; OR=2.050, CI 95%=1.042-4.023). When participants were analyzed according to genotypes TT and TC/CC, C-carriers presented higher cholesterol and triglycerides levels than TT homozygous (p=0.046 and 0.049, respectively). CONCLUSIONS The allele C confers higher total cholesterol and triglycerides levels in dyslipidemic adults. The APOA5 -1131T>C polymorphism is associated with dyslipidemia in male subjects.

Annexin A1 concentrations is decreased in patients with diabetes type 2 and nephropathy

The diabetic nephropathy is considered an inflammatory process characterized by macrophage infiltration observed in every stage of renal involvement. In addition, pro-inflammatory cytokines and adhesion molecules are important in the development of the disease [1]. Annexin A1 (AnxA1) is a 37-kDa protein that regulates various cellular functions and binds to phospholipids in a calcium-dependent manner. Glucocorticoids (GC) regulate expression of ANXA1, which in turn mediates GCs anti-inflammatory actions; however, its expression is also contra-regulated by proinflammatory cytokines, as IL-6. AnxA1 presents anti-inflammatory properties, inhibiting distinct stages of the leukocyte transmigration cascade and interacting directly with NF-κB in an intracellular manner to reduce proinflammatory pathways [2]. AnxA1 has also proresolving properties including promotion of efferocytosis of apoptotic polymorphonuclear leucocytes and is widely present in soluble form in plasma. Some studies have suggested that AnxA1 deficiency may contribute to the etiology of inflammatory diseases [3,4]. We evaluated the AnxA1 concentrations in T2D patients with and without nephropathy and the correlation with IL-6 concentrations. We studied 4 T2D patients without nephropathy (mean age = 46 ± 12 years, 3 women) and 35 T2D patients with nephropathy (mean age = 56 ± 8 years, 31 women), recruited from Santa Casa Hospital (Belo Horizonte, Minas Gerais, Brazil) in the period of June 2012 to

IL-6, TNF-α, and IL-10 levels/polymorphisms and their association with type 2 diabetes mellitus and obesity in Brazilian individuals

OBJECTIVE This study aimed to investigate the association of plasma TNF-α, IL-6, and lL-10 levels and cytokine gene polymorphisms [TNF-α (-308 G→A), IL-6 (-174 C→G) and IL-10 (-1082 A→G, -819 T→C and -592 A→C)] in type 2 diabetes mellitus (T2DM) and obese patients. SUBJECTS AND METHODS One hundred and two T2DM patients and 62 controls were included in this study. Cytokine plasma levels were measured by the Cytometric Bead Array method. Genotyping was carried out by the polymerase chain reaction. RESULTS IL-6 levels were significantly different between T2DM patients and controls. Interestingly, IL-6 levels were higher in T2DM patients with BMI > 30 kg/m2 compared with other patients and obese controls. The genotype and allele frequencies were similar between patients and controls. In the T2DM group, the SNP IL-10 -819 T/C showed a difference between the cytokine level and genotypes: IL-10 level in the TT genotype was significantly higher when compared to CC genotype. CONCLUSIONS These results suggest an association between IL-6 levels and obesity, and IL-10 levels and the SNP -819 T/C in T2DM. Knowledge of these variants in T2DM might contribute to a better understanding of the role of inflammation in the etiology and progression of this disease.

Circulating microparticles levels are increased in patients with diabetic kidney disease: A case-control research

BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with chronic lowgrade inflammation. Microparticles (MPs) are extracellular microvesicles released during apoptosis and cellular activation. The MPs pro-coagulant and pro-inflammatory activities are involved in endothelial dysfunction observed in T2DM patients. This study aimed to evaluate the circulating MPs profile in T2DM patients with diabetic kidney disease (DKD) and correlate it with clinical and laboratorial parameters. METHODS MPs derived from platelets (PMPs), leukocytes (LMPs), endothelial cells (EMPs), and expressing tissue factor (TFMPs) were measured by flow cytometry, in plasma of 39 DKD patients and 30 non-diabetic controls. RESULTS We observed higher PMPs, LMPs, EMPs, and TFMPs (all p<0.0001) levels in case group as compared to controls. For patients with DKD, circulating MPs levels were influenced by gender, but not by obesity status nor by T2DM onset. Fasting glucose and 25-hydroxyvitamin D levels showed correlation with circulating MPs levels in both groups. CONCLUSIONS These results suggest that type 2 diabetes mellitus patients with DKD presented higher circulating MPs levels - PMPs, LMPs, EMPs, and TFMPs - which correlated with metabolic alterations.

Vitamin D receptor polymorphisms and the polycystic ovary syndrome: A systematic review

Polycystic ovary syndrome (PCOS) is the most frequent endocrinological disorder that affects women of reproductive age, leading to metabolic alterations, such as hyperandrogenism, obesity, menstrual irregularities, insulin resistance, and polycystic ovaries. The etiology remains unclear, but several genetic and environmental factors have been correlated with manifestations of this syndrome. Vitamin D plays important roles in metabolic pathways affected by PCOS, including calcium homeostasis, the insulin pathway, and sex hormone synthesis. Vitamin D concentration has been related with the severity of this disorder, and vitamin D receptor polymorphisms have been shown in some studies to have an association with some of the patterns presented by PCOS. The objective of this study is to provide an up‐to‐date review about vitamin D receptor polymorphisms and their association with PCOS.

Visfatin levels are decreased in advanced stages of diabetic nephropathy

Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil, Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil, Colégio Técnico – COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, São Paulo, Brazil, and Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Polymorphisms in vitamin D receptor gene, but not vitamin D levels, are associated with polycystic ovary syndrome in Brazilian women

Abstract This study aimed to investigate the association between vitamin D (VitD) levels, polymorphisms in VDR gene (ApaI, BsmI, FokI, and TaqI) and the polycystic ovary syndrome (PCOS) in a group of Brazilian women. A total of 100 patients with PCOS and 100 control women were included. The quantification of 25-hydroxyvitamin D (25(OH)D) was performed in high-performance liquid chromatography (HPLC). Polymorphisms on VDR gene were performed by PCR-RFLP. The BsmI AG genotype was more frequent in PCOS group, while the GG genotype was more frequent in the control group (p = .007). The frequency of the Taql CC genotype was higher in PCOS group, while the CT genotype was the most frequent in the control group (p = .021). Mean serum VitD levels were similar between the groups. However, there was a negative correlation between VitD levels and Ferriman-Gallwey score (p = .031, r = −.260) in the PCOS group. The TaqI and BsmI polymorphisms were associated with PCOS. Moreover, VitD levels are associated with the clinical hyperandrogenism. The data suggest the role of VitD in PCOS development and its complications.

Haptoglobin levels are influenced by Hp1–Hp2 polymorphism, obesity, inflammation, and hypertension in type 2 diabetes mellitus

BACKGROUND Type 2 diabetes mellitus (T2DM) is an inflammatory condition associated to obesity and increased oxidative stress. Haptoglobin (Hp) is an acute phase reactant that scavenges extracorpuscular hemoglobin from circulation and prevents heme-iron oxidative damage. OBJECTIVE To assess the association between Hp levels and Hp1-Hp2 gene polymorphism and clinical and laboratory parameters in patients with T2DM. METHODS The study sample consisted of 102 T2DM patients and 62 controls. Hp plasma levels were measured using an ELISA assay, and Hp genotyping was performed using a specific two-step allelic polymerase chain reaction. RESULTS Hp levels were higher in T2DM patients as compared to controls (p=0.005). T2DM patients with high blood pressure had higher Hp levels than patients without this comorbidity (p=0.021). Obese T2DM patients had higher Hp levels as compared to obese controls (p=0.009) and to non-obese T2DM patients (p=0.003). The Hp1-Hp1 genotype was showed to be associated to T2DM according to additive (OR=3.038, 95% CI 1.127-8.192; p=0.036) and dominant model (OR=0.320, 95% CI 0.118-0.839; p=0.010), but Hp2 allele carriers contributed with higher Hp levels in T2DM as compared to controls. Waist circumference (p=0.002), BMI (p=0.001), and IL-6 (p=0.012), and hs-CRP (p=0.001) levels positively correlated with Hp levels in the T2DM group. CONCLUSION These results suggest that Hp levels are influenced by Hp1-Hp2 polymorphism, obesity, inflammatory status, and high blood pressure in T2DM.