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  • 1
    Online Resource
    Online Resource
    A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 7 ( 2018-07-01), p. 1414-1427
    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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db17-0914
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 2
    Online Resource
    Online Resource
    Long-term Outcomes With Islet-Alone and Islet-After-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation Consortium: The CIT-08 Study
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 12 ( 2022-12-01), p. 2967-2975
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 12 ( 2022-12-01), p. 2967-2975
    Abstract: To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia. RESEARCH DESIGN AND METHODS This was a prospective interventional and observational cohort study of islet-alone (n = 48) and islet-after-kidney (n = 24) transplant recipients followed for up to 8 years after intraportal infusion of one or more purified human pancreatic islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c & lt;7.0%), freedom from severe hypoglycemia, and insulin independence. RESULTS Of the 48 islet-alone and 24 islet-after-kidney transplantation recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84% and 56% for islet-alone and 69% and 49% for islet-after-kidney (P = 0.007) with 77% and 49% of islet-alone and 57% and 35% of islet-after-kidney transplantation recipients maintaining posttransplant HbA1c & lt;7.0% (P = 0.0017); freedom from severe hypoglycemia was maintained at & gt;90% in both cohorts. Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining insulin independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts, and rates of sensitization against HLA were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney transplantation. CONCLUSIONS Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia, with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc21-2688
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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    detail.hit.zdb_id: 441231-X
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  • 3
    Online Resource
    Online Resource
    Genetic Mapping of Disposition Index and Acute Insulin Response Loci on Chromosome 11q
    American Diabetes Association ; 2006
    In:  Diabetes Vol. 55, No. 4 ( 2006-04-01), p. 911-918
    Details
    In: Diabetes, American Diabetes Association, Vol. 55, No. 4 ( 2006-04-01), p. 911-918
    Abstract: Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and β-cell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.21 at 81 cM flanked by markers D11S2371 and D11S2002 (support interval from 71 to 96 cM). In this study, genotyping and analysis of an additional 214 African-American subjects in 21 pedigrees from the IRASFS yielded independent evidence of linkage to DI. When these two datasets were combined, a DI linkage peak was observed with an LOD of 3.89 at 78 cM (support interval from 67 to 89 cM). Fine mapping with 15 additional microsatellite markers in this 11q region for the entire 42 pedigrees resulted in an LOD score of 4.80 at 80 cM near marker D11S937 (support interval from 76 to 84 cM). In these 42 pedigrees, there was also suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002). No evidence of linkage to the insulin sensitivity index (Si) was observed. Nine positional candidate genes were evaluated for association to DI and AIR. Among these candidates, single nucleotide polymorphisms (SNPs) in muscle glycogen phosphorylase showed evidence of association with DI (P & lt; 0.011). In addition, SNPs in the pyruvate carboxylase gene showed evidence of association (P & lt; 0.002) with AIR. Further analysis of these candidate genes, however, did not provide evidence that these SNPs accounted for the evidence of linkage to either DI or AIR. These detailed genetic analyses provide strong evidence of a DI locus on 11q in African-American pedigrees, with additional suggestive evidence of independent AIR loci in the same region.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.55.04.06.db05-0813
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2006
    detail.hit.zdb_id: 80085-5
    detail.hit.zdb_id: 1501252-9
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