Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis
Open accessAbstract
The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy.
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In a model of STZ-induced insulin-deficient diabetes during pregnancy, hyperglycemia inhibits maturation of fetal offspring cardiomyocytes.
“Using a model of STZ-induced insulin-deficient diabetes during pregnancy, Nakano et al. demonstrated that hyperglycemia promotes the proliferation of fetal offspring cardiomyocytes while maturation was inhibited [117].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [117]
The Results section ('Hyperglycemia promotes the proliferation and inhibits the maturation of cardiomyocytes in utero'; page unavailable) reports increased fetal cardiomyocyte mitotic activity and findings consistent with delayed maturation in diabetic pregnancies. But the pregnancy model used Akita mice with an Ins2 mutation, not STZ-induced diabetes, so the claim misidentifies the model. (LLM, conf=0.93)
Experimental — accuracy not yet measuredIn a model of STZ-induced insulin-deficient diabetes during pregnancy, hyperglycemia promotes proliferation of fetal offspring cardiomyocytes.
“Using a model of STZ-induced insulin-deficient diabetes during pregnancy, Nakano et al. demonstrated that hyperglycemia promotes the proliferation of fetal offspring cardiomyocytes while maturation was inhibited [117].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [117]
The Results section (“Hyperglycemia promotes the proliferation and inhibits the maturation of cardiomyocytes in utero”; page not supplied) reports increased fetal cardiomyocyte mitotic activity and reduced maturation during diabetic pregnancy. But the pregnancy model used Akita mice with an Ins2 mutation, not STZ-induced diabetes; the claimed model is therefore unsupported. (LLM, conf=0.93)
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Self-citation
- Authors
- Nakano, H., Minami, I., Braas, D., Pappoe, H., Wu, X., Sagadevan, A., Vergnes, L., Fu, K., Morselli, M., Dunham, C., Ding, X., Stieg, A. Z., Gimzewski, J. K., Pellegrini, M., Clark, P. M., Reue, K., Lusis, A. J., Ribalet, B., Kurdistani, S. K., Christofk, H., Nakatsuji, N., & Nakano, A.
- Affiliations
- University of California, Los Angeles (US)
- Kyoto University (JP)
- California NanoSystems Institute (US)
- Corresponding author
- Nakano, Haruko
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-12-12
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5726851
- OpenAlex
- W2774527609
- Cited by
- 195
- References
- 54
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 26 · 2023: 28 · 2022: 37 · 2021: 36 · 2020: 16 · 2019: 15 · 2018: 7
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Oppenheimer Foundation
- University of California, Los Angeles (Center for Duchenne Muscular Dystrophy, Pilot and Feasibility Seed Grant program)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR057230)
- National Center for Research Resources (Grant S10RR026744)
- National Institutes of Health (DK094311, CA178415, HL126051, HL124503)
- Hunan University (Chinese Scholarship Council of Chemistry and Chemical Engineering)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- high glucose, cardiomyocyte maturation, nucleotide synthesis, pentose phosphate pathway, diabetes in pregnancy, maternal hyperglycemia, congenital heart disease, cardiomyopathy, pluripotent stem cell-derived cardiomyocytes, fetal heart development
- MeSH terms
- Animals, Cell Differentiation, Female, Glucose, Humans, Mice, Inbred C57BL, Myocardium, Nucleotides, Pentose Phosphate Pathway, Pregnancy, Sweetening Agents, Gene Expression Profiling, Muscle Development, Myocytes, Cardiac, Mice, Embryonic Stem Cells
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