Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice
Autor: | Brian T. Layden, Md. Wasim Khan, Thomas C. Becker, Medha Priyadarshini, Jose Cordoba-Chacon |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty medicine.medical_treatment Mice Transgenic 030209 endocrinology & metabolism Carbohydrate metabolism Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Pregnancy Hexokinase Internal medicine Glucose Intolerance Animals Humans Medicine Molecular Biology business.industry Insulin medicine.disease HKDC1 Mice Inbred C57BL Pregnancy Complications Gestational diabetes Disease Models Animal Glucose HEK293 Cells 030104 developmental biology Endocrinology chemistry Gluconeogenesis Ketone bodies Carbohydrate Metabolism Molecular Medicine Female Insulin Resistance Energy Metabolism business |
Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865:678-687 |
ISSN: | 0925-4439 |
Popis: | 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-hr 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 HKDC1(fl/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. |
Databáze: | OpenAIRE |
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