Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes

The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Dynamic demethylation of the IL2RA promoter during in vitro CD4+ T cell activation in association with IL2RA expression

IL2RA, a subunit of the high affinity receptor for interleukin-2 (IL2), plays a crucial role in immune homeostasis. Notably, IL2RA expression is induced in CD4+ T cells in response to various stimuli and is constitutive in regulatory T cells (Tregs). We selected for our study 18 CpGs located within cognate regulatory regions of the IL2RA locus and characterized their methylation in naive, regulatory, and memory CD4+ T cells. We found that 5/18 CpGs (notably CpG + 3502) show dynamic, active demethylation during the in vitro activation of naive CD4+ T cells. Demethylation of these CpGs correlates with appearance of IL2RA protein at the cell surface. We found no influence of cis located SNP alleles upon CpG methylation. Treg cells show constitutive demethylation at all studied CpGs. Methylation of 9/18 CpGs, including CpG +3502, decreases with age. Our data thus identify CpG +3502 and a few other CpGs at the IL2RA locus as coordinated epigenetic regulators of IL2RA expression in CD4+ T cells. This may contribute to unravel how the IL2RA locus can be involved in immune physiology and pathology

Exploring the risk of hypospadias in children born from mothers living close to a vineyard

International audienceHypospadias (H) is a common birth defect affecting the male urinary tract. It has been suggested that exposure to endocrine disrupting chemicals might increase the risk of H by altering urethral development. However, whether H risk is increased in places heavily exposed to agricultural pesticides, such as vineyards, remains debated and difficult to ascertain. The objective of the work is to test the possible association of H with residential proximity to vineyards. Residential address at birth of 8,766 H cases born 1980-2011 was taken from 17 specialized surgery centers. The geographical distribution of vineyards was obtained from the European Land Parcel Identification System (LPIS) and the distance of address to the nearest vineyard was computed. A first estimate of the variation of H relative risk with distance to vineyards was obtained using as controls 13,105 cryptorchidism (C) cases operated during the same period in the same centers. A separate estimate was obtained from a case-control study using "virtual controls" (VC) defined as points of the map sampled to match the demographic distribution of births within the recruitment territories of the study centers. Non-exposed patients were defined as those with a residence between 5,000 and 10,000 m from the closest vineyard. The residential distance to vineyard was smaller for H than for C cases (p<10 −4). We found 42/8766 H cases (0.48%) and 50/13,105 C cases (0.38%) born to mothers living within 20 m of a vineyard. The odds ratios for H were 2.48 (CI: 1.0 to 5.1) and 2.4 (CI: 1.3 to 4.4), vs C or vs VC, respectively, when pregnant mothers lived 10-20 m from a vineyard. In conclusion, our study supports that children born to mothers living close to a vineyard have a twofold increased risk of H. For environmental research, the use of VC provides an alternative to classical case control technique

Fetal growth is associated with CpG methylation in the P2 promoter of the IGF1 gene

Abstract Background There are many reasons to think that epigenetics is a key determinant of fetal growth variability across the normal population. Since IGF1 and INS genes are major determinants of intrauterine growth, we examined the methylation of selected CpGs located in the regulatory region of these two genes. Methods Cord blood was sampled in 159 newborns born to mothers prospectively followed during their pregnancy. A 142-item questionnaire was filled by mothers at inclusion, during the last trimester of the pregnancy and at the delivery. The methylation of selected CpGs located in the promoters of the IGF1 and INS genes was measured in cord blood mononuclear cells collected at birth using bisulfite-PCR-pyrosequencing. Results Methylation at IGF1 CpG-137 correlated negatively with birth length (r = 0.27, P = 3.5 × 10−4). The same effect size was found after adjustment for maternal age, parity, and smoking: a 10% increase in CpG-137 methylation was associated with a decrease of length by 0.23 SDS. Conclusion The current results suggest that the methylation of IGF1 CpG-137 contributes to the individual variation of fetal growth by regulating IGF1 expression in fetal tissues

Additional file 5: of Fetal growth is associated with the CpG methylation of the P2 promoter of the IGF1 gene

Figure S4. Relation between CpG methylation and birth length (SDS) at the IGF1 promoter 1 and 2. (A) at IGF1 P1 promoter, we observed no significant correlation of birth length with the studied CpGs, (B) at IGF1 P2 promoter, only two CpGs other that CpG-137 showed a weak correlation with birth length. The correlation between CpG-224 (%) and birth length (SDS) is described by the equation: Birth length = − 0.014*[CpG-224 methylation] + 0.43 (r = 0.17, P = 0.03). The correlation between CpG-218 (%) and birth length (SDS) is described by the equation: Birth length = − 0.016*[CpG-218 methylation] + 0.58 (r = 0.2, P = 0.02). (PPTX 752 kb

Additional file 3: of Fetal growth is associated with the CpG methylation of the P2 promoter of the IGF1 gene

Figure S2. Correlation matrix of methylation values (%) at the CG located in the P1 and P2 promoters of the IGF1 gene in newborns patients. Pearson correlation coefficient is indicated in bold, and P value below. (PPTX 88 kb

Additional file 6: of Fetal growth is associated with the CpG methylation of the P2 promoter of the IGF1 gene

Figure S5. Relationship between insulin rs689 genotype and birth weight (sds) and birth length (sds). Birth weight (sds) and birth length (sds) are independent from the rs 689 genotypes. (PPTX 161 kb

Additional file 4: of Fetal growth is associated with the CpG methylation of the P2 promoter of the IGF1 gene

Figure S3. Relationship between promoter CG methylation and genotypes. (A) Methylation at CpGs-137 of the IGF1 P2 promoter is independent from the rs35767 genotypes. (B) Methylation at CpGs-206 and CpG-180 in insulin promoter is closely dependent on rs689 alleles. (PPTX 242 kb