Circulating levels of fibroblast growth factor 21 in early-stage diabetic kidney disease.

AIMS/PURPOSE: Fibroblast growth factor 21 (FGF21), a hepatoadipokine with pleiotropic metabolic regulatory actions, is emerging as a novel biomarker of progressive nephropathy. We sought to evaluate circulating FGF21 and its association with clinical and biochemical characteristics as well as the urinary albumin excretion (UAE) rates in a population of patients with type 2 diabetes (T2D) with or without microalbuminuria and their matched healthy controls. METHODS: Cross-sectionally, 130 consecutive individuals comprising patients with T2D with (n = 44) or without (n = 44) microalbuminuria and their healthy controls (n = 42) were recruited for analysis. Various demographic, clinical and biochemical parameters were assessed. RESULTS: Serum FGF21 levels were significantly elevated in patients with microalbuminuria [median (interquartile range, IQR): 269.50 (188.50) pg/mL] compared to their normoalbuminuric peers with T2D [median (IQR): 103.50 (75.75) pg/mL] and nondiabetic people [median (IQR): 99.00 (126.75) pg/mL]. While serum FGF21, diastolic blood pressure and duration of diabetes mellitus (DDM) were independently associated with microalbuminuria in the baseline logistic regression model, FGF21 and DDM emerged as significant correlates in the multivariate adjusted model (OR for FGF21 = 1.060, 95% CI = 1.011-1.110, P < .016). CONCLUSIONS: Serum FGF21 level is strongly associated with early-stage diabetic kidney disease in the high-risk population of patients with T2D (particularly with circulating FGF21 values rising above 181 pg/mL). The association of serum FGF21 with subclinical stages of diabetic nephropathy may unearth perspectives on early detection and prevention of the advanced stages of chronic diabetes microvascular complications through effective FGF21-targeted therapy.

The comparative effect of pioglitazone and metformin on serum osteoprotegerin, adiponectin and intercellular adhesion molecule concentrations in patients with newly diagnosed type 2 diabetes: a randomized clinical trial.

AIM: The etiologic role of inflammatory pathways in the development of diabetic complications, especially cardiovascular events, has been established. The anti-inflammatory role of metformin and pioglitazone has been described; however, no study to date has compared the efficacy of these common oral agents in this regard. In this study, the authors aimed to compare the anti-inflammatory properties of pioglitazone and metformin, with respect to their effect on serum concentrations of highly sensitive C-reactive protein (hsCRP), osteoprotegerin (OPG), intercellular adhesion molecule-1 (ICAM-1) and adiponectin. METHODS: In an open-label randomized clinical trial, 117 patients with newly diagnosed type 2 diabetes mellitus were visited; 84 fulfilled the inclusion criteria, and were randomly allocated to 2 arms receiving either 1,000 mg/d metformin or 30 mg/d pioglitazone, respectively. Biochemical assessments were made at baseline and the end of the 3 months trial. RESULTS: Significant reduction in FPG, insulin and HbA1c in women and men of both arms were observed. Log-hsCRP values significantly decreased in both arms. A decreasing, but non-significant trend in log-OPG levels was observed in women of the metformin arm (p=0.063). A greater reduction in log-ICAM levels was identifiable in men receiving pioglitazone compared to the other arm (p=0.008); in addition, the same trend was observed in log-OPG values (p=0.029). Nonetheless, reduction in log-ICAM and log-OPG levels was comparable between the 2 arms. A significant increase in adiponectin was observed in both men and women in the pioglitazone arm (p<0.001), whereas changes were non-significant in the metformin arm. CONCLUSION: Remarkably, patients receiving pioglitazone revealed more significant reduction in inflammatory markers.

Comparative effects of metformin and pioglitazone on YKL-40 in type 2 diabetes: a randomized clinical trial.

PURPOSE: Metformin and pioglitazone are believed to exert their long-term benefits by means of amelioration of chronic low-grade inflammation, a key event in development of diabetes and its long-term complications. The present trial was designed to investigate the comparative efficacy of the two anti-diabetes medications on serum concentrations of YKL-40, a novel marker of inflammation. METHODS: In a parallel-group, open-label, randomized trial setting (ClinicalTrials.gov Identifier No. NCT01521624), 84 newly diagnosed, medication-naïve type 2 diabetes patients were assigned to metformin 1,000 mg daily (n = 42) or pioglitazone 30 mg daily (n = 42). Serum concentrations of YKL-40, along with highly sensitive C-reactive protein, indices of glycemic control and lipid profile were measured at baseline and after 3 months. RESULTS: In the analyzed sample (metformin = 40, pioglitazone = 42), both medications were equally effective with regard to control of hyperglycemia, and hsCRP reduction (p > 0.05). However, metformin caused a significant decline in weight (p = 0.005), BMI (p = 0.004), and total cholesterol levels (p = 0.028) of the patients. Metformin also significantly reduced YKL-40 concentrations after 3 months (1.90 ± 17 vs. 1.66 ± 0.15 µg/L, p = 0.019). The amount of change in the pioglitazone arm did not reach statistical significance (2.18 ± 0.14 vs. 2.25 ± 0.16 µg/L, p = 0.687). When compared, metformin was significantly more effective than pioglitazone with respect to YKL-40 reduction in both univariate (p = 0.020, effect size = 6.7%) and multivariate models (p = 0.047, effect size = 5.7%). CONCLUSIONS: Metformin is more effective in reduction of YKL-40 concentration in short term and the effect seems to be independent of degree of glycemic control, or hsCRP reduction.

Visit-to-visit blood pressure variability is related to albuminuria variability and progression in patients with type 2 diabetes.

Recent studies have suggested that visit-to-visit variability of blood pressure (BP) is correlated with microalbuminuria in patients with diabetes, independent of mean pressure. We investigated the contribution of BP variability to albuminuria progression in normoalbuminuric type 2 diabetes patients. BP and urinary albumin excretion of patients were assessed in each visit during a median follow-up of 31 months. Variability was assessed using standard deviation, coefficient of variation, standard deviation independent of mean, peak, average real variability, and average real variability independent of mean. Of 194 patients enrolled, 31 subjects (16.0%) developed microalbuminuria. Systolic blood pressure (SBP) variability indices (except for coefficient of variation and average real variability) were significant predictors of microalbuminuria in multivariate Cox regression models (hazard ratio ranging from 2.02 to 2.76). The same was not observed for diastolic blood pressure. Using linear regression, SBP variability significantly correlated with some but not all indices of albuminuria variability. Peak SBP was the strongest predictor of albuminuria variability in multivariate models (standardized beta ranging from 0.216 to 0.339). In conclusion, visit-to-visit variability of SBP is an independent risk factor for development of microalbuminuria in patients with diabetes, and is associated with an increased variability in albuminuria.

Comparison of osteoprotegerin and vascular endothelial growth factor in normoalbuminuric Type 1 diabetic and control subjects.

BACKGROUND: The aim of the current study was to evaluate the association of osteoprotegerin and vascular endothelial growth factor (VEGF) with glycemic indices and diabetes status. METHODS: A total of 44 normoalbuminuric Type 1 diabetic patients and 44 healthy control subjects, matched for age, body mass index, sex ratio, and lipid measures were enrolled. Univariate and multivariate logistic regression analyses were used to determine the association of osteoprotegerin and VEGF with diabetes status. Further, linear regression analysis was performed to investigate the roles of osteoprotegerin and VEGF as determinants of glycated hemoglobin (HbA1c). RESULTS: Osteoprotegerin and VEGF were significantly elevated in diabetic subjects (2.76±0.85 vs 2.26±0.75 pmol/l and 187.1±92.7 vs 125.9±52.3 pg/ml, respectively, p<0.01) and were positively correlated with glycemic indices (i.e. fasting plasma glucose and HbA1c, p<0.001). After controlling for possible confounding factors, odds ratios (confidence interval) of osteoprotegerin and VEGF for diabetes were 2.532 (1.003-6.392) and 1.021 (1.002-1.041), respectively (p<0.05). Further, linear regression analysis revealed that the association of osteoprotegerin with HbA1c is independent of VEGF and vice versa (p<0.001). CONCLUSION: Osteoprotegerin and VEGF are elevated in normoalbuminuric Type 1 diabetic subjects and are independently associated with glycemic indices and diabetes status.

HLA-DRB and HLA-DQA/HLA-DQB allele and haplotype frequencies in Iranian patients with aggressive periodontitis.

BACKGROUND AND OBJECTIVE: Genetic backgrounds play a key role in susceptibility to and protection against a spectrum of periodontal diseases. Like other infectious diseases, the human leukocyte antigen (HLA) have been found to be associated with periodontitis. This study aimed to investigate differences in allele and haplotype frequencies of HLA class II antigens in a sample of Iranian patients with aggressive periodontitis compared with a healthy control group. MATERIAL AND METHODS: Fifty unrelated patients with aggressive periodontitis and 130 healthy volunteers were enrolled in this study. HLA genotyping for HLA-DRB, HLA-DQA1 and HLA-DQB1 was performed using the PCR with sequence-specific primers. Allele and haplotype frequencies were compared across groups. RESULTS: The frequencies of HLA-DQA1*03:01, HLA-DQB1*03:02 and HLA-DQB1*03:05 alleles, as well as that of the HLA-DRB1*04:01 allele, were significantly higher in patients with aggressive periodontitis compared with control subjects (p = 0.01, p = 0.04, p = 0.05 and p = 0.04, respectively). In contrast, the frequency of the HLA-DQB1*0603 allele was significantly lower in patients with aggressive periodontitis compared with control subjects (p = 0.006; odds ratio = 0.20). With regard to haplotype association, a significantly higher frequency of two haplotypes - HLA-DRB1*04:01/HLA-DQA1*03:01/HLA-DQB1*03:02 and HLA-DRB1*16:01/HLA-DQA1*01:03/HLA-DQB1*05:01 - was observed in patients with aggressive periodontitis compared with healthy controls (p = 0.01, odds ratio = 2.56 and p = 0.05, odds ratio = 5.38, respectively). CONCLUSION: These results provide additional evidence that class II HLA polymorphisms, particularly in the DQ locus, are associated with protection against and susceptibility to aggressive periodontitis.

Gender-dependent effects of metformin on vaspin and adiponectin in type 2 diabetes patients: a randomized clinical trial.

The aim of the study was to assess the effects of metformin on serum concentrations of vaspin and adiponectin in diabetes. Randomized clinical trial of 99 newly diagnosed, medication-naïve, type 2 diabetes patients (NCT01521624) was carried out. Patients were randomly assigned to either metformin 1 000 mg daily plus advice for exercise and lifestyle modification (n=50) or modification alone (n=49). A third group of 50 normoglycemic subjects were also enrolled to compare adipokine concentrations between healthy and diabetes subjects. Serum concentrations of adipokines were measured at baseline and after 12 weeks using ELISA method. Healthy subjects had significantly higher adiponectin levels, but lower concentrations of serum vaspin (p<0.001 in all cases). Vaspin and adiponectin concentrations were 23% and 26% higher in women compared with men. Vaspin dropped significantly after 3-month metformin therapy only in women (1.36 vs. 0.98, p=0.003 in women and 1.31 vs. 1.20, p=0.335 in men). Metformin therapy did not change adiponectin concentration in neither women nor men of the case group (12.66 vs. 12.44 p=0.699 in women and 10.13 vs. 10.94 p=0.253 in men). Comparing case and control groups, metformin decreased vaspin levels more significantly than lifestyle modification in the final multivariate model after controlling for potential confounders only in women (p=0.002) but not men (p=0.896). Conversely, adiponectin levels increased more significantly in the control group, again only in women (p=0.012 and 0.579 for women and men, respectively). Our findings suggest that metformin therapy reduces vaspin concentration in a gender-specific manner. Metformin exerts little benefit in increasing adiponectin levels in diabetes patients.