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Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice.

Publication ,  Journal Article
Khan, MW; Priyadarshini, M; Cordoba-Chacon, J; Becker, TC; Layden, BT
Published in: Biochim Biophys Acta Mol Basis Dis
March 1, 2019

Hexokinase domain containing 1, a recently discovered putative fifth hexokinase, is hypothesized to play key roles in glucose metabolism. Specifically, during pregnancy in a recent genome wide association study (GWAS), a strong correlation between HKDC1 and 2-h plasma glucose in pregnant women from different ethnic backgrounds was shown. Our earlier work also reported diminished glucose tolerance during pregnancy in our whole body HKDC1 heterozygous mice. Therefore, we hypothesized that HKDC1 plays important roles in gestational metabolism, and designed this study to assess the role of hepatic HKDC1 in whole body glucose utilization and insulin action during pregnancy. We overexpressed human HKDC1 in mouse liver by injecting a human HKDC1 adenoviral construct; whereas, for the liver-specific HKDC1 knockout model, we used AAV-Cre constructs in our HKDC1fl/fl mice. Both groups of mice were subjected to metabolic testing before and during pregnancy on gestation day 17-18. Our results indicate that hepatic HKDC1 overexpression during pregnancy leads to improved whole-body glucose tolerance and enhanced hepatic and peripheral insulin sensitivity while hepatic HKDC1 knockout results in diminished glucose tolerance. Further, we observed reduced gluconeogenesis with hepatic HKDC1 overexpression while HKDC1 knockout led to increased gluconeogenesis. These changes were associated with significantly enhanced ketone body production in HKDC1 overexpressing mice, indicating that these mice shift their metabolic needs from glucose reliance to greater fat oxidation and ketone utilization during fasting. Taken together, our results indicate that hepatic HKDC1 contributes to whole body glucose disposal, insulin sensitivity, and aspects of nutrient balance during pregnancy.

Duke Scholars

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Published In

Biochim Biophys Acta Mol Basis Dis

DOI

EISSN

1879-260X

Publication Date

March 1, 2019

Volume

1865

Issue

3

Start / End Page

678 / 687

Location

Netherlands

Related Subject Headings

  • Pregnancy Complications
  • Pregnancy
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Insulin Resistance
  • Humans
  • Hexokinase
  • HEK293 Cells
 

Citation

APA
Chicago
ICMJE
MLA
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Khan, M. W., Priyadarshini, M., Cordoba-Chacon, J., Becker, T. C., & Layden, B. T. (2019). Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice. Biochim Biophys Acta Mol Basis Dis, 1865(3), 678–687. https://doi.org/10.1016/j.bbadis.2018.11.022
Khan, Md Wasim, Medha Priyadarshini, Jose Cordoba-Chacon, Thomas C. Becker, and Brian T. Layden. “Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice.Biochim Biophys Acta Mol Basis Dis 1865, no. 3 (March 1, 2019): 678–87. https://doi.org/10.1016/j.bbadis.2018.11.022.
Khan MW, Priyadarshini M, Cordoba-Chacon J, Becker TC, Layden BT. Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice. Biochim Biophys Acta Mol Basis Dis. 2019 Mar 1;1865(3):678–87.
Khan, Md Wasim, et al. “Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice.Biochim Biophys Acta Mol Basis Dis, vol. 1865, no. 3, Mar. 2019, pp. 678–87. Pubmed, doi:10.1016/j.bbadis.2018.11.022.
Khan MW, Priyadarshini M, Cordoba-Chacon J, Becker TC, Layden BT. Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice. Biochim Biophys Acta Mol Basis Dis. 2019 Mar 1;1865(3):678–687.

Published In

Biochim Biophys Acta Mol Basis Dis

DOI

EISSN

1879-260X

Publication Date

March 1, 2019

Volume

1865

Issue

3

Start / End Page

678 / 687

Location

Netherlands

Related Subject Headings

  • Pregnancy Complications
  • Pregnancy
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Insulin Resistance
  • Humans
  • Hexokinase
  • HEK293 Cells