Genetic and epigenetic studies of diabetes and diabetic nephropathy with focus on the IGF-IGFBP axis

Diabetes and diabetic nephropathy (DN) are complex diseases reflecting a complex interplay between genetic and non-genetic factors. The insulin-like growth factor (IGF) - IGF binding protein (IGFBP) axis plays an important role in the development of diabetes and DN. Recent reports have demonstrated that genetic polymorphisms in this axis are associated with diabetes and DN. However, the information of epigenetic study is very limited. In this study, we selected four genes from this axis including IGF1, IGF2, IGFBP1 and IGF2BP2 to evaluate their genetic and epigenetic associations with diabetes and DN. In parallel, we analyzed the serum protein levels. SNP rs35767 in the IGF1 gene promoter region has been reported to be associated with insulin resistance and circulating IGF-I levels. In Study I, we analyzed IGF1 DNA methylation levels at CpG sites in the promoter region including this SNP and measured serum IGF-I concentration in Swedish subjects with normal glucose tolerance (NGT) or type 2 diabetes (T2D). Data suggested that increased DNA methylation in the gene promoter and decreased circulating IGF-I levels are associated with T2D. IGFBP-1 is produced in liver and mainly regulated by insulin. Clinical observations have demonstrated that high levels of circulating IGFBP-1 are associated with T1D, while low serum levels are associated with the risk of T2D. There is a CpG island at the promoter and 5’-untranlated region (5’-UTR) of the IGFBP1 gene. We analyzed IGFBP1 DNA methylation levels in Swedish T2D patients (Study II) and T1D patients with or without DN (Study III). Results demonstrated that IGFBP1 DNA methylation levels were decreased in T1D patients but increased in T2D patients in comparison with NGT subjects. Furthermore, decreased and increased IGFBP-1 serum levels were respectively associated with T2D and T1D. The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to diabetes and DN. The protein encoded IGF2BP2 binds to 5'-UTR of the imprinting IGF2 gene, which is located on chromosome 11p15.5. In Study IV, we genotyped SNPs rs10770125 (A/G) and rs4402960 (G/T) in the IGF2 and IGF2BP2 genes respectively. Diabetes patients with or without DN and NGT subjects from GoKinD, Czech and Swedish populations were enrolled in this study. Data showed that the IGF2BP2 polymorphism rs4402960 was associated with T2D. This IGF2BP2 polymorphism and rs10770125 in the IGF2 gene were found to be associated with DN in male T1D patients. In conclusion, our studies provide evidence that the IGF1, IGF2, IGFBP1 and IGF2BP2 genes have genetic and epigenetic effects in diabetes and DN. To better understand the importance of our findings, further investigations of tissue specific DNA methylation levels and their impacts on translated proteins are needed

Cardiovascular Autonomic Neuropathy Is an Independent Risk Factor for Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes

Aim. This study aimed to evaluate the association between cardiovascular autonomic neuropathy (CAN) and left ventricular diastolic dysfunction (LVDD) in type 2 diabetes patients. Methods. 315 type 2 diabetes patients from inpatients of Drum Tower Hospital were included and classified into no CAN (NCAN), possible CAN (PCAN), and definite CAN (DCAN) based on cardiovascular autonomic reflex tests. The left ventricular diastolic function was assessed by tissue Doppler imaging echocardiography. Results. The distribution of NCAN, PCAN, and DCAN was 11.4%, 51.1%, and 37.5%, respectively. The proportion of LVDD increased among the groups of NCAN, PCAN, and DCAN (39.4%, 45.3%, and 68.0%, = 0.001). Patients with DCAN had higher filling pressure ( / ratio) (10.9 ± 2.7 versus 9.4 ± 2.8, = 0.013) and impaired diastolic performance ( ) (6.8 ± 1.7 versus 8.6±2.4, = 0.004) compared with NCAN. CAN was found to be an independent risk factor for LVDD from the multivariate regression analysis (OR = 1.628, = 0.009, 95% CI 1.131-2.344). Conclusions. Our results indicated that CAN was an independent risk marker for the presence of LVDD in patients with diabetes. Early diagnosis and treatment of CAN are advocated for preventing LVDD in type 2 diabetes

A Polymorphic Microdeletion in the RGS9 Gene Suppresses PTB Binding and Associates with Obesity

Objective: RGS9 is a member of the family of Regulators of G-Protein Signaling (RGS) proteins defined by the presence of an RGS domain which can accelerate the GTPase-activity of G protein Gα subunits. An insertion/deletion (I/D) polymorphism of the nucleotide sequence TTTCT (rs3215227) has been identified in the human RGS9 gene, which matches the consensus high affinity binding motif for the ubiquitously expressed RNA binding Polypyrimidine Tract Binding Protein (PTB). In this study, we evaluate the genetic association and functional relevance of this polymorphism in type 2 diabetes and obesity. Subjects and methods: We genotyped a larger population of 9272 Chinese and Malaysian individuals for the RGS9 I/D polymorphism using TaqMan allelic discrimination protocols. We found that the D allele of the RGS9 polymorphism was associated with a decreased prevalence of obesity in women (P=0.003, OR=0.753 95%CI 0.625-0.906) and girls (P=0.002, OR=0.604 95%CI 0.437-0.835). The association was moderate in boys (P=0.038, OR=0.724 95%CI 0.533-0.983) and not significant in men. Furthermore, we found that the transcript deletion variant exhibited a 10-fold reduction in PTB binding in vitro and that the splicing of the deletion variant was less affected by PTB co-expression. Conclusions: We provide genetic and biochemical data to support a genetic role of RGS9 in obesity but unlikely in T2D. The RGS9 I/D polymorphism influence the post-transcriptional processing of the gene through an altered affinity for the splicing factor PTB and are associated with obesity

Differential regulation of clathrin and its adaptor proteins during membrane recruitment for endocytosis

In plants, clathrin-mediated endocytosis (CME) is dependent on the function of clathrin and its accessory heterooligomeric adaptor protein complexes, ADAPTOR PROTEIN2 (AP-2) and the TPLATE complex (TPC), and is negatively regulated by the hormones auxin and salicylic acid (SA). The details for how clathrin and its adaptor complexes are recruited to the plasma membrane (PM) to regulate CME, however, are poorly understood. We found that SA and the pharmacological CME inhibitor tyrphostin A23 reduce the membrane association of clathrin and AP-2, but not that of the TPC, whereas auxin solely affected clathrin membrane association, in Arabidopsis (Arabidopsis thaliana). Genetic and pharmacological experiments revealed that loss of AP2 mu or AP2 sigma partially affected the membrane association of other AP-2 subunits and that the AP-2 subunit AP2 sigma, but not AP2 mu, was required for SA-and tyrphostin A23-dependent inhibition of CME. Furthermore, we show that although AP-2 and the TPC are both required for the PM recruitment of clathrin in wild-type cells, the TPC is necessary for clathrin PM association in AP-2-deficient cells. These results indicate that developmental signals may differentially modulate the membrane recruitment of clathrin and its core accessory complexes to regulate the process of CME in plant cells

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

New susceptibility loci associated with kidney disease in type 1 diabetes

WOS:000309817900008Diabetic 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.Peer reviewe

No-reference quality evaluator of transparently encrypted images

In the past years, various encrypted algorithms have been proposed to fully or partially protect the multimedia content in view of practical applications. In the context of digital TV broadcasting, transparent encryption only protects partial content and fulfills both security and quality requirements. To date, only a few reference-based works have been reported to evaluate the quality of transparently encrypted images. However, these works are incapable of reference-unavailable conditions. In this paper, we conduct the first attempt that proposes a novel quality evaluator in the absence of reference images. The key strategy of proposed metric lies in extracting features by considering the motivation of transparently encrypted images. Specifically, given that encrypted images prevent the content to be easily recognized, several features, including correlation coefficient, information entropy and intensity statistic, are preliminarily extracted to estimate visual recognizability. Meanwhile, considering that encrypted images avoid to be in extremely low-quality, we also capture many features to measure the distortions on multiple quality-sensitive image attributes, such as naturalness, structure, and texture. Finally, the quality evaluator is built by bridging all extracted features and corresponding quality scores via a regression module. Experimental results demonstrate that the proposed method is superior to the mainstream no-reference quality evaluation methods designed for synthetically distorted images and possesses a close approximation to state-of-the-art reference-based methods designed for encrypted images