T-cadherin gene variants are associated with nephropathy in subjects with type 1 diabetes

International audienceBackground. High plasma adiponectin levels are associated with diabetic nephropathy (DN). T-cadherin gene (CDH13) variants have been shown to be associated with adiponectin levels. We investigated associations between allelic variations of CDH13 and DN in subjects with type 1 diabetes.Methods.Two CDH13 polymorphisms were analysed in 1297 Caucasian subjects with type 1 diabetes from the ‘Survival Genetic Nephropathy’ (SURGENE) (n = 340, 10-year follow-up),‘Genesis France–Belgium’ (GENESIS) (n = 501, 5-year follow-up for n ¼ 462) and ‘Génétique de la Néphropathie Diabétique’ (GENEDIAB) (n = 456, 9-year follow-up for n =283) cohorts. Adiponectin levels were measured in plasma samples from GENESIS and GENEDIAB cohorts.Results. Pooled analysis of GENEDIAB and GENESIS studies showed that baseline plasma adiponectin levels were higher insubjects with established/advanced DN at inclusion (P<0.0001) and in subjects who developed end-stage renal disease (ESRD) at follow-up (P<0.0001). The minor allele of rs3865188 was associated with lower adiponectin levels (P¼0.006). rs11646213 [odds ratio (OR) 1.47; 95% confidence interval (CI) 1.18–1.85; P=0.0009] and rs3865188 (OR 0.71; 95% CI 0.57–0.90; P=0.004) were associated with baseline prevalence of established/advanced DN. These polymorphisms were also associated with the risk of ESRD (0.006 < P<0.03).The association between rs11646213 (but not rs3865188) and renal function remained significant after adjustment for plasma adiponectin. In SURGENE, rs11646213 [hazard ratio (HR) 1.69; 95% CI 1.01–2.71; P=0.04] and rs3865188 (HR 0.74; 95% CI 0.55–0.99; P=0.04) were associated with risk of renal events (defined as progression to more severe DN stages).Conclusions.Plasma adiponectin levels are associated with the prevalence of DN and the incidence of ESRD in patients with type 1 diabetes. CDH13 polymorphisms are also associated with the prevalence and incidence of DN, and with the incidence of ESRD in these patients. The association between CDH13 and DN may be due to pleiotropic effects, both dependent and independent of plasma adiponectin levels

Allelic variations in the vitamin D receptor gene, insulin secretion and parents' heights are independently associated with height in obese children and adolescents

Polymorphisms in the VDR gene were reported to be associated with variations in intrauterine and postnatal growth and with adult height, but also with other traits that are strongly correlated such as the BMI, insulin sensitivity, insulin secretion and hyperglycemia. Here, we assessed the impact of VDR polymorphisms on body height and its interactions with obesity- and glucose tolerance-related traits in obese children and adolescents. We studied 173 prepubertal (Tanner's stage 1) and 146 pubertal (Tanner's stages 2-5) obese children who were referred for a weight-loss program. Three single nucleotide polymorphisms were genotyped: rs1544410 (BsmI), rs7975232 (ApaI) and rs731236 (TaqI). BsmI and TaqI genotypes were significantly associated with height in pubertal children, but the associations did not reach statistical significance in prepubertal children. In stepwise regression analyses, the lean body mass, insulin secretion, BsmI or TaqI genotypes and the father's and the mother's height were independently and positively associated with height in pubertal children. These covariables accounted for 46% of the trait variance. The height of homozygous carriers of the minor allele of BsmI was 0.65 z-scores (4 cm) higher than the height of homozygous carriers of the major allele (P=.0006). Haplotype analyses confirmed the associations of the minor alleles of BsmI and TaqI with increased height. In conclusion, VDR genotypes were significantly associated with height in pubertal obese children. The associations were independent from the effects of confounding traits, such as the body fat mass, insulin secretion, insulin sensitivity and glucose tolerance. (C) 2012 Elsevier Inc. All rights reserved.FAPESP, BrazilFAPESP (Brazil)Societe Francophone du Diabete (SFD - Alfediam)Societe Francophone du Diabete (SFD Alfediam)Association Diabete Risque Vasculaire (ADRV), FranceAssociation Diabete Risque Vasculaire (ADRV), FranceCNPq, BrazilCNPq (Brazil

ABCG8 polymorphisms and renal disease in type 2 diabetic patients

International audienc

Allelic variations in the CYBA gene of NADPH oxidase and risk of kidney complications in patients with type 1 diabetes

International audienc

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man.

International audienceThe kallikrein-kinin system has been suggested to participate in the control of glucose metabolism. Its role and the role of angiotensin-I-converting enzyme, a major kinin-inactivating enzyme, are however the subject of debate. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on the development of insulin resistance and diabetes in mice and man. Mice with inactivation of the TK gene were fed a high-fat diet (HFD) for 3 months, or crossed with obese, leptin-deficient (ob/ob) mice to generate double ob/ob-TK-deficient mutants. In man, a loss-of-function polymorphism of the TK gene (R53H) was studied in a large general population cohort tested for insulin resistance, the DESIR study (4843 participants, 9 year follow-up). Mice deficient in TK gained less weight on the HFD than their WT littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks on the HFD compared with standard on the diet, but TK deficiency had no influence on these parameters. Likewise, ob-TK⁻/⁻ mice had similar GTT and ITT responses to those of ob-TK⁺/⁺ mice. TK deficiency had no effect on blood pressure in either model. In humans, changes over time in BMI, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective 53H-coding TK allele. The incidence of diabetes was not influenced by this allele. These data do not support a role for the TK-kinin system, protective or deleterious, in the development of insulin resistance and diabetes

Plasma Adrenomedullin and Allelic Variation in the ADM Gene and Kidney Disease in People With Type 2 Diabetes

International audienceProduction of adrenomedullin (ADM), a vasodilator peptide, increases in response to ischemia and hypoxia in the vascular wall and the kidney. This may be an adaptive response providing protection against organ damage. We investigated the hypothesis that ADM has a nephroprotective effect in two prospective cohorts of patients with type 2 diabetes recruited in France. The highest tertile of plasma MR-proADM (a surrogate for ADM) concentration at baseline was associated with the risk of renal outcomes (doubling of plasma creatinine concentration and/or progression to end-stage renal disease) during follow-up in both cohorts. Four SNPs in the ADM gene region were associated with plasma MR-proADM concentration at baseline and with eGFR during follow-up in both cohorts. The alleles associated with lower eGFR were also associated with lower plasma MR-proADM level. In conclusion, plasma MR-proADM concentration was associated with renal outcome in patients with type 2 diabetes. Our data suggest that the ADM gene modulates the genetic susceptibility to nephropathy progression. Results are consistent with the hypothesis of a reactive rise of ADM in diabetic nephropathy, blunted in risk alleles carriers, and with a nephroprotective effect of ADM. A possible therapeutic effect of ADM receptor agonists in diabetic renal disease would be worth investigating

Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation

International audienceBackgroundFetal exposure to hyperglycemia impacts negatively kidney development and function.ObjectiveOur objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring.DesignTwenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion.ResultsGlobally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)—a key enzyme involved in gene expression during early development–was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls.ConclusionAlterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function

Distribution of β-values for selected subjects (cases and controls) and CpG sites.

<p>Panel A: distribution of β-values for 26,069 CpG sites for four randomly selected subjects (two among cases, and two among control subjects). Panel B: Distribution of β-values at selected CpG sites for all 57 study subjects.</p