BACKGROUND: Recent work in Pima Indians, a population with high rates of obesity and type 2 diabetes mellitus (T2DM), demonstrated that human leukocyte antigen haplotype DRB1*02 carriers have an increased acute insulin response and decreased risk for the development of T2DM, implicating loss of self-tolerance in the pathogenesis of T2DM. Advances in genomic sequencing have made T-cell receptor repertoire analysis a practical mode of investigation. METHODS: High-throughput sequencing of T-cell receptor complementarity-determining region 3 was carried out in male Pima Indians with normal glucose regulation (n = 11; age = 31 ± 8 years; %fat = 30.2 ± 8.7%) and the protective DRB1*02 haplotype versus those with T2DM without DRB1*02 (n = 7; age = 34 ± 8 years; %fat = 31.2 ± 4.7%). Findings were partially replicated in another cohort by assessing the predictive ability of T-cell receptor variation on risk of T2DM in Pima Indian men (n = 27; age = 28.9 ± 7.1 years; %fat = 28.8 ± 7.1%) and women (n = 20; age = 29 ± 7.0 years; %fat = 37.1 ± 6.8%) with baseline normal glucose regulation but without the protective haplotype who were invited to follow-up examinations as frequently as every 2 years where diabetes status was assessed by a 75-g oral glucose tolerance test. Of these subjects, 13 developed diabetes. RESULTS: T-cell receptor complementarity-determining region 3 length was shorter in those with T2DM, and a one-nucleotide decrease in complementarity-determining region 3 length was associated with a nearly threefold increase in risk for future diabetes. The frequency of one variable gene, TRBV7-8, was higher in those with T2DM. A 1% increase in TRBV7-8 frequency was associated with a greater than threefold increase in diabetes risk. CONCLUSIONS: These results indicate that T-cell autoimmunity may be an important component in progression to T2DM in Pima Indians.
BACKGROUND: Recent work in Pima Indians, a population with high rates of obesity and type 2 diabetes mellitus (T2DM), demonstrated that human leukocyte antigen haplotype DRB1*02 carriers have an increased acute insulin response and decreased risk for the development of T2DM, implicating loss of self-tolerance in the pathogenesis of T2DM. Advances in genomic sequencing have made T-cell receptor repertoire analysis a practical mode of investigation. METHODS: High-throughput sequencing of T-cell receptor complementarity-determining region 3 was carried out in male Pima Indians with normal glucose regulation (n = 11; age = 31 ± 8 years; %fat = 30.2 ± 8.7%) and the protective DRB1*02 haplotype versus those with T2DM without DRB1*02 (n = 7; age = 34 ± 8 years; %fat = 31.2 ± 4.7%). Findings were partially replicated in another cohort by assessing the predictive ability of T-cell receptor variation on risk of T2DM in Pima Indian men (n = 27; age = 28.9 ± 7.1 years; %fat = 28.8 ± 7.1%) and women (n = 20; age = 29 ± 7.0 years; %fat = 37.1 ± 6.8%) with baseline normal glucose regulation but without the protective haplotype who were invited to follow-up examinations as frequently as every 2 years where diabetes status was assessed by a 75-g oral glucose tolerance test. Of these subjects, 13 developed diabetes. RESULTS: T-cell receptor complementarity-determining region 3 length was shorter in those with T2DM, and a one-nucleotide decrease in complementarity-determining region 3 length was associated with a nearly threefold increase in risk for future diabetes. The frequency of one variable gene, TRBV7-8, was higher in those with T2DM. A 1% increase in TRBV7-8 frequency was associated with a greater than threefold increase in diabetes risk. CONCLUSIONS: These results indicate that T-cell autoimmunity may be an important component in progression to T2DM in Pima Indians.
Authors: Barbara Brooks-Worrell; Christiane S Hampe; Erica G Hattery; Brenda Palomino; Sahar Z Zangeneh; Kristina Utzschneider; Steven E Kahn; Mary E Larkin; Mary L Johnson; Kieren J Mather; Naji Younes; Neda Rasouli; Cyrus Desouza; Robert M Cohen; Jean Y Park; Hermes J Florez; Willy Marcos Valencia; Ali Shojaie; Jerry P Palmer; Ashok Balasubramanyam Journal: Diabetes Date: 2022-01-21 Impact factor: 9.337
Authors: Ye Gao; Yiran Wang; Xiao Zhai; Yifei He; Rong Chen; Jingjing Zhou; Ming Li; Qijin Wang Journal: PLoS One Date: 2017-09-19 Impact factor: 3.240
Authors: Dana C Crawford; Jessica N Cooke Bailey; Kristy Miskimen; Penelope Miron; Jacob L McCauley; John R Sedor; John F ƠToole; William S Bush Journal: AMIA Jt Summits Transl Sci Proc Date: 2018-05-18
Authors: Barbara M Brooks-Worrell; Ashley H Tjaden; Sharon L Edelstein; Brenda Palomino; Kristina M Utzschneider; Silva Arslanian; Kieren J Mather; Thomas A Buchanan; Kristen J Nadeau; Karen Atkinson; Elena Barengolts; Steven E Kahn; Jerry P Palmer Journal: Front Immunol Date: 2021-04-26 Impact factor: 7.561