Regulatable production of insulin from primary-cultured hepatocytes: Insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

Lu, D; Tamemoto, H; Shibata, H; Saito, I; Takeuchi, T

doi:10.1038/sj.gt.3300677

Cited by 35Pancreatic function and diabetesVirus-based gene therapy researchViral Infectious Diseases and Gene Expression in Insects

Regulatable production of insulin from primary-cultured hepatocytes: Insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

Lu, D, Tamemoto, H, Shibata, H, Saito, I, Takeuchi, T·1998·Gene Therapy

DOI 10.1038/sj.gt.3300677

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Abstract

To utilize hepatocytes for insulin-producing surrogate cells, we devised a regulatory secretion system by placing proinsulin DNA under the regulatable promoter for phosphoenolpyruvate carboxykinase (PEPCK). The expression of PEPCK is down-regulated by insulin, and up-regulated by cAMP and glucagon. To express insulin in hepatocytes, we constructed an adenoviral insulin expression system. After infection, the hepatocytes secreted immunoreactive insulin (IRI) at an increasing rate. IRI secretion increased over four-fold upon stimulation with 300 microM cAMP and 500 microM of the cAMP-dependent phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). This increase was also observed with glucagon and IBMX. Production was augmented two-fold by the addition of wortmannin, phosphatidylinositol (PI)-3-kinase inhibitor, suggesting that inhibitory insulin signaling to the PEPCK promoter may be mediated through PI-3-kinase. Addition of exogenous insulin to the culture decreased insulin mRNA expression remarkably on Northern blot. Thus, by using a PEPCK promoter for insulin expression, we were able to up-regulate insulin production from hepatocytes with cAMP and glucagon, and down-regulate with insulin itself.

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Authors: Lu, D., Tamemoto, H., Shibata, H., Saito, I., & Takeuchi, T.
Affiliations: Gunma University (JP)
Institute of Medical Science, The University of Tokyo (JP)
ORCID: Shibata, H
Saito, I
Takeuchi, T
Venue: Gene Therapy
Publisher: Springer Science and Business Media LLC
Published: 1998-07-01
Volume: 5
Issue: 7
Pages: 888-895
ISSN: 0969-7128 (ISSN-L)
1476-5462
DOI: 10.1038/sj.gt.3300677
OpenAlex: W2319240083
Cited by: 35
References: 45
Citations by year: 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2016: 1 · 2013: 2 · 2012: 2
FWCI: 4.30
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Gene Therapy (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords: insulin production, primary hepatocytes, insulin-producing cells, cyclic AMP, glucagon, insulin signaling, PI3-kinase, wortmannin, 3-isobutyl-1-methylxanthine, adenoviral gene transfer, insulin secretion regulation
MeSH terms: Wortmannin, Cyclic AMP, Adenoviridae, Androstadienes, Animals, Cells, Cultured, Gene Expression Regulation, Genetic Vectors, Glucagon, Insulin, Insulin Antagonists, Liver, Male, Phosphoenolpyruvate Carboxykinase (GTP), Proinsulin, 1-Methyl-3-isobutylxanthine, Genetic Therapy, Rats, Wistar, Gene Transfer Techniques, Rats

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Regulatable production of insulin from primary-cultured hepatocytes: Insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

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