title: Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium.
abstract: Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMAIR] and of β-cell function [HOMAB]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [SI] and acute insulin response [AIRg]) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMAB-AIRg: ρG = 0.28-0.73; HOMAIR-SI: ρG = -0.73 to -0.83) with increased heritability for the dynamic measure AIRg Significant association of variants with dynamic measures (P < 8.77 × 10(-4)) was observed. A pattern of superior performance of AIRg was observed for well-established loci including MTNR1B (P = 9.46 × 10(-12)), KCNQ1 (P = 1.35 × 10(-4)), and TCF7L2 (P = 5.10 × 10(-4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIRg (P < 1.38 × 10(-9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically "closer" to causal pathways and provide insight into the discrete mechanisms of action.
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC nallred@wakehealth.edu.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Preventative Medicine, Keck School of Medicine of USC, Los Angeles, CA Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchanan
authors.affiliation: Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA.
authors.forename: Anny H
authors.initials: AH
authors.lastname: Xiang
authors.affiliation: Department of Preventative Medicine, Keck School of Medicine of USC, Los Angeles, CA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Raffel
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Yii-Der Ida
authors.initials: YD
authors.lastname: Chen
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.affiliation: Department of Epidemiology, University of Colorado Denver, Aurora, CO Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO.
authors.forename: Tasha
authors.initials: T
authors.lastname: Fingerlin
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Preventative Medicine, Keck School of Medicine of USC, Los Angeles, CA Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D007328:Insulin