title: HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use.
abstract: In a recent genome-wide association study, hexokinase domain-containing protein 1, or HKDC1, was found to be associated with gestational glucose levels during 2-hour glucose tolerance tests at 28 weeks of pregnancy. Because our understanding of the mediators of gestational glucose homeostasis is incomplete, we have generated the first transgenic mouse model to begin to understand the role of HKDC1 in whole-body glucose homeostasis. Interestingly, deletion of both HKDC1 alleles results in in utero embryonic lethality. Thus, in this study, we report the in vivo role of HKDC1 in whole-body glucose homeostasis using a heterozygous-deleted HKDC1 mouse model (HKDC1(+/-)) as compared with matched wild-type mice. First, we observed no weight, fasting or random glucose, or fasting insulin abnormalities with aging in male and female HKDC1(+/-) mice. However, during glucose tolerance tests, glucose levels were impaired in both female and male HKDC1(+/-) mice at 15, 30, and 120 minutes at a later age (28 wk of age). These glucose tolerance differences also existed in the female HKDC1(+/-) mice at earlier ages but only during pregnancy. And finally, the impaired glucose tolerance in HKDC1(+/-) mice was likely due to diminished whole-body glucose use, as indicated by the decreased hepatic energy storage and reduced peripheral tissue uptake of glucose in HKDC1(+/-) mice. Collectively, these data highlight that HKDC1 is needed to maintain whole-body glucose homeostasis during pregnancy but also with aging, possibly through its role in glucose use.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Anton E
authors.initials: AE
authors.lastname: Ludvik
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Pusec
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Medha
authors.initials: M
authors.lastname: Priyadarshini
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Angueira
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Cong
authors.initials: C
authors.lastname: Guo
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Amy
authors.initials: A
authors.lastname: Lo
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Korri S
authors.initials: KS
authors.lastname: Hershenhouse
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Ding
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Reddy
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: William L
authors.initials: WL
authors.lastname: Lowe
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (A.E.L., C.M.P., M.P., A.R.A., K.S.H., W.L.L., B.T.L.), Department of Pathology (A.L., G.-Y.Y.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Biostatistics and Bioinformatics (T.E.R.), and Center for Genomic and Computational Biology (C.G., T.E.R.), Duke University Medical School, and University Program in Genetics and Genomics (C.G.), Duke University, Durham, North Carolina 27710; Department of Pathology (X.D.), Loyola University Chicago, Maywood, Illinois 60153; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Layden
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006593:Hexokinase / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*
chemical_list: D006593:Hexokinase; C000620869:Hkdc1 protein, mouse; D005947:Glucose