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Träfflista för sökning "WFRF:(Groop Leif) srt2:(2015-2019)"

Sökning: WFRF:(Groop Leif) > (2015-2019)

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1.
  • van Zuydam, NR, et al. (författare)
  • A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
  • 2018
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 67:7, s. 1414-1427
  • Tidskriftsartikel (refereegranskat)abstract
    • Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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2.
  • Ahluwalia, Tarunveer S., et al. (författare)
  • A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
  • 2019
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 62:2, s. 292-305
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6). Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
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3.
  • Andersson, Anneli, et al. (författare)
  • Continuous and simultaneous determination of venous blood metabolites
  • 2017
  • Ingår i: Talanta. - : Elsevier BV. - 0039-9140. ; 171, s. 270-274
  • Tidskriftsartikel (refereegranskat)abstract
    • Metabolic syndrome is associated with cardiovascular disease, type 2 diabetes mellitus (T2DM) and prediabetes. Metabolic syndrome is a cluster of interrelated clinical disorders. Difficulties in regulating glucose levels in blood are implicated in many of these disorders. Lactate, another energy metabolite, is produced under anaerobic conditions and can be used to monitor the balance between aerobic and anaerobic metabolism. Tested together, these metabolite levels can provide pro-diagnostic information that improves patient outcomes. Glucose and lactate were determined continuously and simultaneously in whole blood using a dual-channel thermal biosensor device in which one channel employed glucose oxidase for glucose analysis in comparison with lactate oxidase for lactate analysis in the others. No detectable clogging or interference was observed using venous blood samples. The linear detection range for both the glucose and lactate assays was 0.5–45 mM. The sampling rate of up to 24 samples per hour with assay cycle time of 2.5 min was achieved. Comparative analysis between our device and the HemoCue method showed an excellent correlation. The device was stable for hundreds of injections over a period of 45 days. The broad linear range, fast response and detection sensitivity are satisfactory for the clinical requirements, e.g. for diabetic or cardiovascular patients in intensive care units or surgical operation, where the tight control of blood glucose can decrease morbidity or mortality.
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4.
  • Berglund, Lisa, et al. (författare)
  • Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.
  • 2016
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 239-254
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.
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5.
  • Gao, Xiang, et al. (författare)
  • Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats
  • 2018
  • Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 6:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion, and affects -cell turnover. This study aimed at evaluating if some of the beneficial effects of GIP on glucose homeostasis can be explained by modulation of islet blood flow. Anesthetized Sprague-Dawley rats were infused intravenously with different doses of GIP (10, 20, or 60ng/kg*min) for 30min. Subsequent organ blood flow measurements were performed with microspheres. In separate animals, islets were perfused exvivo with GIP (10(-6)-10(-12)mol/L) during normo- and hyperglycemia and arteriolar responsiveness was recorded. The highest dose of GIP potentiated insulin secretion during hyperglycemia, but had no effect in normoglycemic rats. The highest GIP concentration decreased blood perfusion of whole pancreas, pancreatic islets, duodenum, colon, liver and kidneys. The decrease in blood flow was unaffected by ganglion blockade or adenosine receptor inhibition. In contrast to this, in single perfused islets GIP induced a dose-dependent arteriolar dilation. Thus, high doses of GIP exert a direct dilatory effect on islet arterioles in isolated islets, but induce a generalized vasoconstriction in splanchnic organs, including the whole pancreas and islets, invivo. The latter effect is unlikely to be mediated by adenosine, the autonomic nervous system, or endothelial mediators.
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7.
  • Meng, Weihua, et al. (författare)
  • A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes
  • 2018
  • Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X. ; 96:7, s. 811-819
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. Results: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10−9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10−8 and 1.23 × 10−8, respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
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8.
  • Ottosson Laakso, Emilia, et al. (författare)
  • Influence of Familial Renal Glycosuria Due to Mutations in the SLC5A2 Gene on Changes in Glucose Tolerance over Time.
  • 2016
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Familial renal glycosuria is an inherited disorder resulting in glucose excretion in the urine despite normal blood glucose concentrations. It is most commonly due to mutations in the SLC5A2 gene coding for the glucose transporter SGLT2 in the proximal tubule. Several drugs have been introduced as means to lower glucose in patients with type 2 diabetes targeting SGLT2 resulting in renal glycosuria, but no studies have addressed the potential effects of decreased renal glucose reabsorption and chronic glycosuria on the prevention of glucose intolerance. Here we present data on a large pedigree with renal glycosuria due to two mutations (c.300-303+2del and p.A343V) in the SLC5A2 gene. The mutations, which in vitro affected glucose transport in a cell line model, and the ensuing glycosuria were not associated with better glycemic control during a follow-up period of more than 10 years. One individual, who was compound heterozygous for mutations in the SLC5A2 gene suffered from severe urogenital candida infections and postprandial hypoglycemia. In conclusion, in this family with familial glycosuria we did not find any evidence that chronic loss of glucose in the urine would protect from deterioration of the glucose tolerance over time.
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10.
  • Sandholm, Niina, et al. (författare)
  • The genetic landscape of renal complications in type 1 diabetes
  • 2017
  • Ingår i: Journal of the American Society of Nephrology. - 1046-6673. ; 28:2, s. 557-574
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4310-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associatedvariants.Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2310-5) and the risk of type 2 diabetes (P=6.1310-4) associated with the risk of diabetic kidney disease.Wealso found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1310-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0310-6), and pentose and glucuronate interconversions (P=3.0310-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
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