Associations between genetic variants and the severity of metabolic syndrome in subjects with type 2 diabetes.

Metabolic syndrome (MetS) includes obesity, dyslipidemia, elevated blood pressure, and dysglycemia. Subjects with type 2 diabetes (T2D) exhibit features of MetS. The etiology of MetS is complex, involving both environmental and genetic factors. In this study, we examined the role of specific candidate genetic variants on the severity of MetS in T2D subjects. A total of 240 T2D subjects aged 35-64 years were recruited. Waist circumstance, plasma triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, and blood pressure were measured to define MetS. Subjects were divided into 4 groups according to MetS components. Target genes involved in fibrotic and inflammatory processes, insulin and diabetes, cell growth and proliferation, and hypertension were genotyped. A total of 13 genes and 103 single-nucleotide polymorphisms (SNPs) were analyzed to evaluate their genetic association with MetS severity in T2D subjects. Univariate ordinal logistic regression using a dominant model (homozygous for the major allele vs carriers of the minor allele) revealed 6 SNP markers within 4 genes with genotypes associated with MetS risk. For the SNP genotypes of rs362551 (SNAP25), rs3818569 (RXRG), rs1479355, rs1570070 (IGF2R), and rs916829 (ABCC8), heterozygotes showed a lower risk of MetS compared with the reference group. In addition, the CC genotype was comparable to the TT genotype for rs3777411. There was no gender-specific effect. In conclusion, our results suggest that among the Han Chinese population, several SNPs increase the risk of severe MetS in T2D subjects. Further study in a large population should be conducted.

Association between retinoid-X receptor-gamma genetic polymorphisms and diabetic retinopathy.

Retinoid-X receptor (RXR) is one of the members of the nuclear hormone receptor superfamily. It forms heterodimers with many nuclear receptors, such as the peroxisome proliferative-activated receptor, which has been proposed to be involved in diabetic complications, including retinopathy. A recent study revealed that RXR-alpha has antioxidant properties and is associated with diabetic retinopathy. We found that the RXR-gamma gene is involved in the pathogenesis of diabetic nephropathy. We also hypothesized that the RXR-gamma gene has a role in the development of diabetic retinopathy. We examined 213 diabetic patients, who were divided into retinopathy or no retinopathy groups. Nine selected single nucleotide polymorphisms (SNPs) in the RXR-gamma gene were evaluated. The diabetic retinopathy group had longer diabetes duration, higher body mass indexes, and higher systolic blood pressure, as well as higher concentrations of fasting plasma glucose, blood urine nitrogen, and creatine. One SNP--rs3818569 of the RXR-gamma gene was found to be associated with increased risk for diabetic retinopathy in both allele and genotype frequencies (P = 0.0023 and 0.0057, respectively). Analysis with multivariate logistic regression revealed that the dominant RXR-gamma GG genotype is a risk factors for the development of diabetic retinopathy (odds ratio = 2.388; 95% confidence interval = 1.17-4.875). We conclude that the RXR-gamma rs3818569 SNP is associated with diabetic retinopathy development in the Taiwanese population.

Eyes absent mediates cross-talk between retinal determination genes and the receptor tyrosine kinase signaling pathway.

Eyes absent (eya) encodes a member of a network of nuclear transcription factors that promotes eye development in both vertebrates and invertebrates. Despite extensive studies, the molecular mechanisms whereby cell-cell signaling pathways coordinate the function of this retinal determination gene network remain unknown. Here, we report that Drosophila Eya function is positively regulated by mitogen-activated protein kinase (MAPK)-mediated phosphorylation and that this regulation extends to developmental contexts independent of eye determination. In vivo genetic analyses, together with in vitro kinase assay results, demonstrate that Eya is a substrate for extracellular signal-regulated kinase, the MAPK acting downstream in the receptor tyrosine kinase (RTK) signaling pathway. Thus, phosphorylation of Eya appears to provide a direct regulatory link between the RTK/Ras/MAPK signaling cascade and the retinal determination gene network.

Differential effects of retinal degeneration on sleep and wakefulness responses to short light-dark cycles in albino mice.

This study characterizes the different response patterns of sleep and wakefulness (W) to short light-dark (LD) cycles in albino mice and examines whether retinal degeneration resulting from prolonged bright light treatment and/or rd/rd mutation alters such response patterns. Eight young male Institute for Cancer Research (ICR) mice with normal eyes, seven young male rd/rd Friend Virus B type (FVB) mice, six young ICR and five young rd/rd FVB mice receiving 48-h bright light treatment, and five older rd/rd FVB mice were implanted with skull and muscle electrodes to record sleep and W. All the mice were maintained in 12-h-12-h LD cycles at baseline and received 2 days of short LD cycle treatment, which included 5-min-5-min LD cycles for a total of 24 cycles presented 4h after lights-on and again 4h after lights-off. All the five mouse groups maintained photo-entrainment of sleep and W rhythms at the baseline and showed a preference for paradoxical sleep (PS) occurrence in the 5-min dark period and non-rapid eye movement sleep (NREMS) in the 5-min light period and a brief alerting effect of light onset on experimental days. Retinal degeneration rising from bright light treatment and/or genetic mutation failed to eliminate or reduce the response of PS and NREMS to short LD cycles, although it enhanced the LD contrast of W, i.e., bright light treatment prolonged the alerting effect of light and the rd mutation increased the suppressing effect of the dark on W. These results suggest that sleep responses to short LD cycles and the brief alerting effect of light were independent of the photoreceptors in the outer retina. Furthermore, the residual photoreceptors in the outer retina and/or the photosensitive cells in the inner retina may actively modulate the effect of light and dark signals on W.

Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). Chronic inflammation and derangement of myocardial energy and lipid homeostasis are common features of DM. The transcription factors of peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, which are important in regulating energy and lipid homeostasis. There are three PPAR isoforms, α, γ, and δ, and their roles have been increasingly recognized to be important in CVD. These three isoforms are expressed in the heart and play pivotal roles in myocardial lipid metabolism, as well as glucose and energy homeostasis, and contribute to extra metabolic roles with effects on inflammation and oxidative stress. Moreover, regulation of PPARs may have significant effects on cardiac electrical activity and arrhythmogenesis. This review describes the roles of PPARs and their agonists in DM cardiomyopathy, inflammation, and cardiac electrophysiology.

In vivo gene delivery into ocular tissues by eye drops of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) polymeric micelles.

The primary objective of this study was to investigate the feasibility of using PEO-PPO-PEO non-ionic copolymeric micelles as a carrier for eye-drop gene delivery of plasmid DNA with lacZ gene in vivo. Using pyrene fluorescence probe methods, zeta potential, and dynamic light scattering test (DLS), the ability of micelle formation of these block copolymers with plasmid was studied. Gene expressions were visualized by both the quality of enzymatic color reaction using X-gal staining and by the quantification of the substrate chlorophenol red galactopyranoside (CPRG) in enucleated eyes on day 2 after gene transfer. In addition, microscopy to identify the types of cell showing uptake and expression of the transferred gene was used. We found that the block polymeric micelles were formed above 0.1% (w/v) of block copolymer with a size of 160 nm and a zeta potential of -4.4 mV. After 2 days of topically delivery three times a day, the most intense gene expression was observed on days 2 and 3. Reporter expression was detected around the iris, sclera, conjunctiva, and lateral rectus muscle of rabbit eyes and also in the intraocular tissues of nude mice upon in vivo topical application for 48 h with a DNA/polymeric micelle formulation. Furthermore, after two enhancement treatments, the transport mechanisms of the block copolymeric micelles were found through endocytosis in tissues by enhancement through the tight junction pathway. Thus, efficient and stable transfer of the functional gene could be achieved with PEO-PPO-PEO polymeric micelles through topical delivery in mice and rabbits. These in vivo experiments indicate the possible potential use of block copolymers for DNA transfer.