Objective:
Type 2 diabetes (T2D) is the primary case of chronic kidney disease (CKD). Inflammation is associated with metabolic dysregulation in patients with T2D and CKD. Tryptophan (TRP) metabolism ...may have relevance to the CKD outcomes and associated symptoms. We investigated the relationships of TRP metabolism with inflammatory markers in patients with T2D and CKD.
Methods:
Data were collected from a well-characterized cohort of type 2 diabetic individuals with all stages of CKD, including patients on hemodialysis. Key TRP metabolites (kynurenine KYN, kynurenic acid KYNA, and quinolinic acid QA), proinflammatory cytokines (tumor necrosis factor-α TNF-α and interleukin-6 IL-6), and C-reactive protein were measured in plasma. The KYN/TRP ratio was utilized as a surrogate marker for indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity.
Results:
There was a significant inverse association between circulating TRP level and stages of CKD (P < 0.0001). Downstream bioactive TRP metabolites KYN, KYNA, and QA were positively and robustly correlated with the severity of kidney disease (P < 0.0001). In multiple linear regression, neither TNF-α nor IL-6 was independently related to KYN/TRP ratio after adjusting for estimated glomerular filtration rate (eGFR). Only TNF-α was independently related to KYN after taking into account the effect of eGFR.
Conclusions:
Chronic kidney disease secondary to T2D may be associated with accumulation of toxic TRP metabolites due to both inflammation and impaired kidney function. Future longitudinal studies to determine whether the accumulation of KYN directly contributes to CKD progression and associated symptoms in patients with T2D are warranted.
The Na-H exchanger NHE performs an electroneutral uptake of NaCl and water from the lumen of the gastrointestinal tract. There are several distinct NHE isoforms, some of which show an altered ...expression in the inflammatory bowel diseases (IBD). In this study, we examined a role of NHE-2 in experimental colitis.
Colitis was induced in male Sprague-Dawley rats by intra-rectal administration of trinitrobenzenesulphonic acid (TNBS). On day 6 post-TNBS, the animals were sacrificed, colonic and ileal segments were taken out, cleaned with phosphate buffered saline and used in this study.
There was a significant decrease in the level of NHE-2 protein as measured by ECL western blot analysis and confocal immunofluorescence microscopy. The levels of NHE-2 mRNA and heteronuclear RNA measured by an end-point RT-PCR and a real time PCR were also decreased significantly in the inflamed colon. However, there was no change in the level of NHE-2 protein in response to in vitro TNF-α treatment of uninflamed rat colonic segment. These changes were selective and localized to the colon as actin, an internal control, remained unchanged. Confocal immunofluorescence microscopy revealed co-localization of NHE-2 and NHE-3 in the brush borders of colonic epithelial cells. Inflamed colon showed a significant increase in myeloperoxidase activity and colon hypertrophy. In addition, there was a significant decrease in body weight and goblet cells' mucin staining in the TNBS treated colon. These changes were not conspicuous in the non-inflamed ileum.
These findings demonstrate suppression of NHE-2 expression on the brush borders in the colonic epithelial cells which is regulated transcriptionally. However a role of TNF-α in the regulation of NHE-2 is discounted in the present model of colitis. This decrease in the NHE-2 expression will lead to a loss of electrolyte and water uptake thus contributing to the symptoms associated with IBD.
Activating transcription factor 6 (ATF6) is important for protective cell response to accumulation of unfolded and misfolded proteins in endoplasmic reticulum, and disturbances of this process can ...contribute to beta-cell apoptosis. We analyzed the structural gene located within a region on 1q21-q23 linked with type 2 diabetes in several populations for variants in the Pima Indians. Functionally important segments of ATF6 were sequenced in 15 diabetic and 15 nondiabetic Pimas and representative single nucleotide polymorphisms (SNPs) tested for association with type 2 diabetes in 900-1,000 subjects. We identified 20 variants including three amino acid substitutions Met(67)Val, Pro(145)Ala, and Ser(157)Pro. Pro(145)Ala and Ser(157)Pro were in a complete linkage disequilibrium and showed a nominal association with type 2 diabetes (P = 0.05; odds ratio 2.3 95% CI 1.0-5.2) and with 30-min plasma insulin during oral glucose tolerance test in 287 nondiabetic individuals (P = 0.045). Although the associations with type 2 diabetes and plasma insulin levels are marginal and their functional consequences are yet unknown, all three amino acid substitutions are located in a functionally important part of ATF6. Because these variants are not unique to the Pimas, it will be feasible to investigate their association with type 2 diabetes in other populations to better evaluate their significance for a predisposition to the disease.
Elevated serum uric acid level is associated with obesity, insulin resistance, diabetes, nephropathy, and hypertension. Epidemiologic studies suggest that serum uric acid levels are heritable. We ...sought to identify chromosomal regions harboring quantitative trait loci that influence serum uric acid in Mexican Americans using data from 644 participants in the San Antonio Family Heart Study. Serum uric acid was found to exhibit significant heritability (0.42) in this population (P = 2 x 10(-7)) after accounting for covariate effects. In addition, genetic correlations between serum uric acid and other cardiovascular risk factors, such as body mass index, waist circumference, systolic BP, and pulse pressure, were identified, suggesting that the genes associated with uric acid level are also associated with these phenotypes. Multipoint linkage analysis identified quantitative trait loci with measurable effects on serum uric acid variability. The highest multipoint logarithm of odds score of 3.3 was found at 133 cM on chromosome 6q22-23, a region that also contains genes that seem to influence familial IgA nephropathy, obesity, BP, insulin resistance, and type 2 diabetes. Given the relationship between uric acid level and these conditions, future studies should investigate potential candidate susceptibility genes found in this region.
Adiponectin is an abundant adipose tissue-derived protein with important metabolic effects. Plasma adiponectin levels are decreased in obese individuals, and low adiponectin levels predict insulin ...resistance and type 2 diabetes. Two variants in the adiponectin gene ACDC have been previously associated with plasma adiponectin levels, obesity, insulin resistance, and type 2 diabetes. To determine the role of genetic variation in ACDC in susceptibility to obesity and type 2 diabetes in Pima Indians, we screened the promoter, exons, and exon-intron boundaries of the gene to identify allelic variants. We identified 17 informative polymorphisms that comprised four common (minor allele frequency >15%) linkage disequilibrium clusters consisting of 1-4 variants each. We genotyped one representative polymorphism from each cluster in 1,338 individuals and assessed genotypic association with type 2 diabetes, BMI, serum lipid levels, serum adiponectin levels, and measures of insulin sensitivity and secretion. None of the ACDC variants were associated with type 2 diabetes, BMI, or measures of insulin sensitivity or secretion. One variant, single nucleotide polymorphism (SNP)-12823, was associated with serum adiponectin levels (P = 0.002), but this association explained only 2% of the variance of serum adiponectin levels. Our findings suggest that these common ACDC polymorphisms do not play a major role in susceptibility to obesity or type 2 diabetes in this population.
Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio ...Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects.
GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G x DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G x DM interaction effects (Model 1) and that included G x DM interaction effects (Model 2, in the case of GFR-CGc).
The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds LOD 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score LOD(C) 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LOD(C) >or=1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q.
We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population.
Background: Elevated serum uric acid is associated with several cardiovascular disease (CVD) risk factors such as hypertension, inflammation, endothelial dysfunction, insulin resistance, ...dyslipidemia, and obesity. However, the role of uric acid as an independent risk factor for CVD is not yet clear.
Objective: The aim of the study was to localize quantitative trait loci regulating variation in serum uric acid and also establish the relationship between serum uric acid and other CVD risk factors in Mexican Americans (n = 848; men = 310, women = 538) participating in the San Antonio Family Heart Study.
Methods: Quantitative genetic analysis was conducted using variance components decomposition method, implemented in the software program SOLAR.
Results: Mean ± sd of serum uric acid was 5.35 ± 1.38 mg/dl. Univariate genetic analysis showed serum uric acid and other CVD risk markers to be significantly heritable (P < 0.005). Bivariate analysis showed significant correlation of serum uric acid with body mass index, waist circumference, waist/hip ratio, total body fat, plasma insulin, serum triglycerides, high-density lipoprotein cholesterol, C-reactive protein, and granulocyte macrophage-colony stimulating factor (P < 0.05). A genome-wide scan for detecting quantitative trait loci regulating serum uric acid variation showed a significant logarithm of odds (LOD) score of 4.72 (empirical LOD score = 4.62; P < 0.00001) on chromosome 3p26. One LOD support interval contains 25 genes, of which an interesting candidate gene is chemokine receptor 2.
Summary: There is a significant genetic component in the variation in serum uric acid and evidence of pleiotropy between serum uric acid and other cardiovascular risk factors.
There is a significant genetic component in the variation in serum uric acid and evidence of pleiotropy between serum uric acid and other cardiovascular risk factors.
Abstract only
Background
The Na‐H exchanger (NHE) perform an electroneutral uptake of NaCl and water from the lumen of the gastrointestinal tract. There are multiple distinct NHE isoforms, some of ...which show an altered expression in the inflammatory bowel diseases (IBD). In this study, we examined a role of NHE‐2 in experimental colitis.
Methods
Colitis was induced in male Sprague‐Dawley rats by intra‐rectal administration of trinitrobenezenesulfonic acid (TNBS). On day 6 post‐TNBS, the animals were sacrificed, colon and ileal segments were taken out, cleaned with phosphate buffered saline and used in this study.
Results
There was a significant decrease in the level of NHE‐2 protein as measured by ECL western blot and confocal immunofluorescence micrometry. The levels of NHE‐2 mRNA and heteronuclear RNA measured by an end‐point RT‐PCR and the real time PCR were also decreased significantly in the inflamed colon. However there was no change in the level of NHE‐2 protein in response to in‐vitro TNF‐α treatment of an uninflamed rat colon. These changes were selective and localized to colon as actin, an internal control remained unchanged. The confocal fluorescence microscopy revealed co‐localization of NHE‐2 and NHE‐3 in the brush borders of the colonic epithelial cells. Inflamed colon showed a significant increase in the myeloperoxidase activity and colon hypertrophy, and a significant decrease in the body weight and goblet cells' mucin staining. These changes were not conspicuous in the non‐inflamed ileum.
Conclusions
These findings demonstrate suppression of NHE‐2 expression on the brush borders in the colonic epithelial cells which is regulated transcriptionally. However a role of TNF‐α in the regulation of NHE‐2 is discounted in the present model of colitis. This decrease in the NHE‐2 expression will lead to a loss of electrolyte and water uptake thus contributing to the symptoms associated with IBD.
Support or Funding Information
The Kuwait University, Research Grant No. YM 12/15. Prof Khan, Anatomy for his help in tissue block preparation for histochemistry and confocal microscopy. Research Core Facility, Health Sciences, the Kuwait University for using their facility to conduct confocal immunofluorescence experiments.
The enzyme 8-oxoguanine glycosylase 1 (OGG1) repairs 8-oxo-2- deoxyguanosine residue (8-oxodG) an oxidatively damaged promutagenic base. Genetic variations in OGG1 gene have been shown to modulate ...DNA repair capacity and are related risk of tumor development. However, epidemiologic findings have been inconsistent. The purpose of this study is to determine whether genetic variants in OGG1 play a role in susceptibility to angiomyolipoma, a benign kidney tumor associated with tuberous sclerosis complex (TSC) patients. To identify genetic variations, all 7 exons of the OGG1 gene were amplified by PCR and sequenced in 22 TSC patients with angiomyolipoma (cases) and 18 controls. By direct sequencing, we identified four missense mutations in OGG1: Arg(45)Gln, Ala(85)Ser, Arg(229)Gln, and Ser(326)Cys. Genotypic association with angiomyolipoma was performed using the measured genotype approach as implemented in the variance component analytical tools. Association analysis showed the presence of significant association (p=0.01) only between the Ser(326)Cys polymorphism of OGG1 and angiomyolipoma. We also assessed the presence of oxidative DNA damage in kidney section from normal healthy subjects, normal kidney tissue from TSC patients and kidney angiomyolipoma tissue from TSC patients by immunostaining for 8-oxodG. 8-OxodG staining was highly abundant in kidney angiomyolipoma tissue from TSC patients compared to weak staining in uninvolved tissue from the same TSC patients or normal kidney from healthy subjects. Taken together, our findings suggest that Ser(326)Cys variant of OGG1 may confer risk for development of angiomyolipomas by increasing oxidative DNA damage.
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