• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    The Effect of Variants in Five Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related Traits

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Winters_umaryland_0373D_10704.pdf
    Size:
    9.057Mb
    Format:
    PDF
    Download
    Author
    Winters, Alexandra Holbrooke
    0000-0003-1215-726X
    Advisor
    Pollin, Toni
    Date
    2016
    Type
    dissertation
    
    Metadata
    Show full item record
    Other Titles
    The Effect of Variants in 5 Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related Traits
    Abstract
    The CDC estimates that 29.1 million Americans have type 2 diabetes, which is currently the seventh leading cause of death in the US. It has been proposed that disordered glucagon regulation is a major contributor to the diabetic phenotype. We hypothesized that variants in five genes in the glucagon pathway are associated with response of diabetes-related glucose, insulin, and body composition traits to three antidiabetic interventions in the DPP and that rare coding variants would be enriched compared to other populations and associated with type 2 diabetes and diabetes-related traits in the Old Order Amish (OOA). We have discovered an association between the GCG variant, rs5649, that is predicted to modify the consensus splice site, with increased baseline-adjusted fasting glucose at one year in the metformin and placebo groups but not in the other two treatment groups, suggesting that it may change the structure of glucagon and decrease the ability of metformin to reduce glucagon signaling. We have performed the only known study of a PCSK2 coding variant common in any population. We found this variant, R430W, and the GCGR variant D458H to be twice as common among OOA individuals with diabetes as those with normal or impaired glucose tolerance, although this difference is not statistically significant. In addition, we examined the relationship between the GCGR coding variant G40S and type 2 diabetes risk that has been previously reported and did not see an association despite being better powered than previous studies because of the increased allele frequency of 14% in the OOA population. Finally, we described the only reported GCGR G40S homozygotes, none of whom have type 2 diabetes. In sum, we have provided data on the effects of variants in five genes in the glucagon pathway that can be used in future work to understand the contribution of the glucagon pathway to type 2 diabetes and to inform the development of antidiabetic treatments targeting this pathway.
    Description
    University of Maryland, Baltimore. Epidemiology and Preventive Medicine. Ph.D. 2016
    Keyword
    diabetes prevention program
    Old Order Amish
    prohormone convertase 2
    Amish
    Diabetes Mellitus, Type 2
    Glucagon
    Proprotein Convertases
    Receptors, Glucagon
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/5464
    Collections
    Theses and Dissertations School of Medicine
    Theses and Dissertations All Schools

    entitlement

     

    Related items

    Showing items related by title, author, creator and subject.

    • Thumbnail

      Genomic Medicine in Diabetes: Improving the Diagnostic Rate of Monogenic diabetes

      Zhang, Haichen; Pollin, Toni; 0000-0002-0615-2836 (2021)
      Monogenic diabetes is an uncommon type of diabetes caused by genetic defects in one of several genes, and it accounts for 1-2% of all diabetes. The primary subtypes are Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, and syndromic diabetes. The correct treatment of each subtype of monogenic diabetes depends on the corresponding disease etiology that can only be confirmed by genetic testing. However, the diagnostic rate of monogenic diabetes is inadequate, mainly due to the overlapping phenotype of monogenic diabetes with type 1 diabetes and type 2 diabetes and lack of awareness among patients and physicians. To improve the diagnostic rate of monogenic diabetes, this project focuses on three aspects: 1) systematically screening of patients for genetic testing; 2) comprehensively re-analyzing next-generation sequencing (NGS) data from multiple diabetes cohorts; 3) assessing the ability of Direct-to-Consumer Genetic Testing (DTC-GT) raw data in detecting GCK-MODY variants. The Personalized Diabetes Medicine Program (PDMP) screened 2,522 patients with diabetes with a simple questionnaire, assigned patients to different algorithm criteria groups based on clinical features, and performed genetic testing on suspected patients. Overall, 38 of 313 patients suspected of monogenic diabetes were tested positive for causative variants. The group of patients diagnosed before age 30 who were not treated with insulin had the highest pick-up rate. The comprehensive re-analysis of NGS panel data in PDMP, including re-classification and updating variant calling algorithm, improved the diagnostic rate from 11.82% to 13.10%. Also, the comparison between exome sequencing (ES) and NGS panel or Sanger sequencing of the Progress for Diabetes Genetics in Youth samples showed ES failed to identify all MODY-causing variants, but re-analysis of ES unfiltered data discovered the missing variants. By analyzing the GCK variants in the 23andMe DTC-GT raw data from 3,044 anonymous volunteers and calculating the ancestry-specific allele frequency of GCK-MODY variants, some of the variants showed higher-than-expected minor allele frequency compared with the large population database. Such inconsistency suggests customers should not use DTC-GT as a supplementary method of clinical genetic testing for GCK-MODY. In a summary, these studies provide practical approaches to improve the diagnostic rate of monogenic diabetes.
    • Thumbnail

      Substance Use Disorders and Type 2 Diabetes Mellitus: Integration of Evidence-Based Diabetes Prevention Program to Promote Quality Health Outcomes in Clients with SUD

      Adejumo, Oluremi A. (2022-10-21)
    • Thumbnail

      Screening Adults with Type II Diabetes in Primary Care for Diabetes Distress

      Laird, Jordan E.; Watson, Melissa D.N.P., C.R.N.A.; Regan, Claire (2023-03-03)
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.