Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase-dependent manner in diabetic mice
Open accessAbstract
Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8-dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes.
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The metabolic improvement from BH4 is at least partially due to NOS3-mediated activation of AMPK in the liver, which suppresses hepatic gluconeogenesis.
“This metabolic improvement was at least partially due to NOS3-mediated activation of AMPK in the liver, which suppressed hepatic gluconeogenesis [292].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [292]
Administration of BH4 to STZ-induced diabetic mice lowers fasting blood glucose levels in an NOS3-dependent manner and improves glucose tolerance and insulin sensitivity in ob/ob mice.
“Administration of BH4, which is known to be oxidized to BH2 in the diabetic state [289-291] and plays an important role in regulating coupled NOS3 activity (vide supra), to STZ-induced diabetic mice lowered fasting blood glucose levels in an NOS3-dependent manner and improved glucose tolerance and insulin sensitivity in ob/ob mice [292].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [292]
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References 49 · Cited by 52
- Authors
- Abudukadier, A., Fujita, Y., Obara, A., Ohashi, A., Fukushima, T., Sato, Y., Ogura, M., Nakamura, Y., Fujimoto, S., Hosokawa, M., Hasegawa, H., & Inagaki, N.
- Affiliations
- Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Kyoto University (JP)
- Nihon University (JP)
- Corresponding author
- Inagaki, Nobuya
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-08-15
- Volume
- 62
- Issue
- 9
- Pages
- 3033-3043
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3749361
- OpenAlex
- W2100127181
- Cited by
- 52
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 11 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 1 · 2015: 5 · 2014: 6 · 2013: 1
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- American Diabetes Association
- Japan Society for the Promotion of Science (23591308)
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- tetrahydrobiopterin, endothelial nitric oxide synthase, hepatic gluconeogenesis, insulin resistance, impaired glucose tolerance, type 2 diabetes, AMP kinase, streptozotocin-induced diabetes, ob/ob mice, eNOS uncoupling, 7,8-dihydrobiopterin, glucose metabolism
- MeSH terms
- Animals, Biopterins, Cells, Cultured, Diabetes Mellitus, Experimental, Gluconeogenesis, Hypoglycemic Agents, Immunohistochemistry, Liver, Male, Mice, Inbred C57BL, Immunoblotting, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, RNA, Small Interfering, Endothelial Cells, Mice, Nitric Oxide Synthase Type III
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