Insulin Sensitivity and Insulin Clearance Are Heritable and Have Strong Genetic Correlation in Mexican Americans

Authors

  • Mark O. Goodarzi,

    Corresponding author
    1. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
    2. Medical Genetics Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
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  • Carl D. Langefeld,

    1. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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  • Anny H. Xiang,

    1. Department of Research and Evaluation, Kaiser Permanente Southern California Medical Group, Pasadena, California, USA
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  • Yii-Der I. Chen,

    1. Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
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  • Xiuqing Guo,

    1. Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
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  • Anthony J. G. Hanley,

    1. Department of Nutritional Sciences and Medicine and Dalla Lana School of Public Health, University of Toronto, Ontario, Canada
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  • Leslie J. Raffel,

    1. Medical Genetics Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
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  • Fouad Kandeel,

    1. Department of Diabetes, Endocrinology and Metabolism, City of Hope, Duarte, California, USA
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  • Jerry L. Nadler,

    1. Department of Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA
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  • Thomas A. Buchanan,

    1. Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
    2. Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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  • Jill M. Norris,

    1. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
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  • Tasha E. Fingerlin,

    1. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
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  • Carlos Lorenzo,

    1. Division of Clinical Epidemiology, University of Texas Health Sciences Center, San Antonio, Texas, USA
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  • Marian J. Rewers,

    1. Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
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  • Steven M. Haffner,

    1. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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  • Donald W. Bowden,

    1. Department of Biochemistry, Centers for Diabetes Research and Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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  • Stephen S. Rich,

    1. Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
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  • Richard N. Bergman,

    1. Diabetes and Obesity Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
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  • Jerome I. Rotter,

    1. Department of Research and Evaluation, Kaiser Permanente Southern California Medical Group, Pasadena, California, USA
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  • Richard M. Watanabe,

    1. Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA
    2. Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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  • Lynne E. Wagenknecht

    1. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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  • Mark O. Goodarzi and Carl D. Langefeld contributed equally to this work.

  • Funding agencies: This research was supported by the National Institutes of Health: GUARDIAN Study (DK085175); IRAS (HL047887, HL047889, HL047890, HL47902); IRAS Family (HL060944, HL061019, HL060919); BetaGene (DK061628); MACAD (HL088457); HTN-IR (HL067974); NIDDM-Athero (HL055798); the Harbor/LA Biomed-Cedars-Sinai GCRC (M01-RR00425), the USC GCRC (M01-RR00043); the UCLA CTSI (UL1TR000124); the USC CTSI (UL1TR000130); the Southern California Diabetes Research Center (DK063491); and research related to insulin clearance (DK079888). TRIPOD was supported by a research grant from Parke Davis Pharmaceutical Research (PD-991-053).

  • Disclosure: The authors have no competing interests relevant to this study.

  • Author contributions: All authors made substantial contributions to conception and design, acquisition of data or analysis and interpretation of data, participated in drafting the article or revising it critically for important intellectual content, and gave final approval of the version to be published.

Abstract

Objective

The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).

Methods

GUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican-American individuals in 1,346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3,925 individuals) using variance components.

Results

Across studies, age, and gender-adjusted heritability of insulin sensitivity (SI, M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P < 0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P < 0.0001); and −0.16 to −0.36 for AIRg and MCRI (P < 0.0001-0.06).

Conclusions

These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.

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