Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle
Abstract
Insulin regulates the activity of key enzymes of glucose metabolism in skeletal muscle by altering transcription or translation or by producing activity-altering modifications of preexisting enzyme molecules. Because of the small size of percutaneous muscle biopsies, these phenomena have been difficult to study in humans. This study was performed to determine how physiological hyperinsulinemia regulates the activities of hexokinase (HK), glycogen synthase (GS), and GLUT-4 in human skeletal muscle in vivo. We determined mRNA abundance, protein content, and activities for these proteins in muscle biopsies before and after a hyperinsulinemic clamp in normal subjects. HK I, HK II, GS, and GLUT-4 were expressed in muscle. HK II accounted for 80% of total HK activity and was increased by insulin from a basal value of 2.11 +/- 0.26 to 3.35 +/- 0.47 pmol.min-1.mg protein-1 (P < 0.05); HK I activity was unaffected. Insulin increased GS activity from 3.85 +/- 0.82 to 6.06 +/- 0.49 nmol.min-1.mg-1 (P < 0.01). HK II mRNA was increased 3.3 +/- 1.3-fold (P < 0.05) by insulin infusion. HK I, GS, and GLUT-4 mRNA and protein were unaffected. Because insulin infusion increased HK II but not GS mRNA, we conclude that HK II and GS may be regulated by insulin by different mechanisms in human skeletal muscle.
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Both hexokinase isoforms are expressed in a variety of cell types; insulin-sensitive cells such as adult muscle cells express primarily HK2, whereas cells that rely heavily on glycolysis such as neurons express predominantly Hk1.
“Although both hexokinase isoforms are expressed in a variety of cell types, cells that are sensitive to insulin, such as adult muscle cells, express primarily HK2, whereas cells that rely heavily on glycolysis for energy production, such as neurons, express predominantly Hk1 (Mandarino et al., 1995;Wilson, 2003).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Mandarino et al., 1995
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Self-citation
- Authors
- Mandarino, L. J., Printz, R. L., Cusi, K. A., Kinchington, P., O'Doherty, R. M., Osawa, H., Sewell, C., Consoli, A., Granner, D. K., & DeFronzo, R. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 1995-10-01
- Volume
- 269
- Issue
- 4
- Pages
- E701-E708
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2145707410
- Cited by
- 124
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 8 · 2023: 3 · 2022: 6 · 2021: 5 · 2019: 2 · 2018: 7 · 2017: 2 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 6 · 2012: 2
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK47936, DK 24092, R01DK047936, DK35107)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- hexokinase 2, glycogen synthase, GLUT4, insulin regulation, hyperinsulinemic-euglycemic clamp, skeletal muscle, glucose metabolism, mRNA expression, enzyme activity
- MeSH terms
- Adult, Blood Glucose, Female, Glycogen Synthase, Hexokinase, Humans, Insulin, Male, Monosaccharide Transport Proteins, Muscle Proteins, Muscles, RNA, Messenger, Glucose Clamp Technique, Glucose Transporter Type 4
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