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Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production

Proinsulin-transferrin (ProINS-Tf) fusion protein was evaluated for its in vivo pharmacokinetics, efficacy, and mechanism. Our previous studies have shown that ProINS-Tf was converted to active insulin-transferrin (INS-Tf) via the transferrin (Tf)-receptor–mediated pathway in hepatoma cells. We hypo...

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Autores principales: Wang, Yan, Shao, Juntang, Zaro, Jennica L., Shen, Wei-Chiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994961/
https://www.ncbi.nlm.nih.gov/pubmed/24353179
http://dx.doi.org/10.2337/db13-0973
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author Wang, Yan
Shao, Juntang
Zaro, Jennica L.
Shen, Wei-Chiang
author_facet Wang, Yan
Shao, Juntang
Zaro, Jennica L.
Shen, Wei-Chiang
author_sort Wang, Yan
collection PubMed
description Proinsulin-transferrin (ProINS-Tf) fusion protein was evaluated for its in vivo pharmacokinetics, efficacy, and mechanism. Our previous studies have shown that ProINS-Tf was converted to active insulin-transferrin (INS-Tf) via the transferrin (Tf)-receptor–mediated pathway in hepatoma cells. We hypothesized that this fusion protein can be administered as a prodrug and be converted to a biologically active protein with specificity for the liver versus other insulin (INS)-sensitive tissues (muscle and adipose). Administration as an inactive prodrug with liver-specific action compared with other INS-sensitive tissues conceivably reduces negative side effects seen with other INS analogs. In this report, the data show that ProINS-Tf exhibited a slow, but sustained, in vivo hypoglycemic efficacy and long plasma half-life. The fusion protein showed activity in the liver, as evidenced by decreased expression of two key hepatic glucose production (HGP) enzymes, PEPCK and glucose-6-phosphatase, and increased glycogen levels under feeding conditions. Furthermore, the INS receptor (IR) phosphorylation (activation) in liver and muscle tissues was compared with postinjection of INS or ProINS-Tf. While INS activated IR in both the liver and muscle, ProINS-Tf only showed activation in the liver. Thus, ProINS-Tf fusion protein can potentially be administered as a prodrug with sustained Tf-mediated activation and selectivity in inhibiting HGP.
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spelling pubmed-39949612015-05-01 Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production Wang, Yan Shao, Juntang Zaro, Jennica L. Shen, Wei-Chiang Diabetes Pharmacology and Therapeutics Proinsulin-transferrin (ProINS-Tf) fusion protein was evaluated for its in vivo pharmacokinetics, efficacy, and mechanism. Our previous studies have shown that ProINS-Tf was converted to active insulin-transferrin (INS-Tf) via the transferrin (Tf)-receptor–mediated pathway in hepatoma cells. We hypothesized that this fusion protein can be administered as a prodrug and be converted to a biologically active protein with specificity for the liver versus other insulin (INS)-sensitive tissues (muscle and adipose). Administration as an inactive prodrug with liver-specific action compared with other INS-sensitive tissues conceivably reduces negative side effects seen with other INS analogs. In this report, the data show that ProINS-Tf exhibited a slow, but sustained, in vivo hypoglycemic efficacy and long plasma half-life. The fusion protein showed activity in the liver, as evidenced by decreased expression of two key hepatic glucose production (HGP) enzymes, PEPCK and glucose-6-phosphatase, and increased glycogen levels under feeding conditions. Furthermore, the INS receptor (IR) phosphorylation (activation) in liver and muscle tissues was compared with postinjection of INS or ProINS-Tf. While INS activated IR in both the liver and muscle, ProINS-Tf only showed activation in the liver. Thus, ProINS-Tf fusion protein can potentially be administered as a prodrug with sustained Tf-mediated activation and selectivity in inhibiting HGP. American Diabetes Association 2014-05 2014-04-12 /pmc/articles/PMC3994961/ /pubmed/24353179 http://dx.doi.org/10.2337/db13-0973 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Pharmacology and Therapeutics
Wang, Yan
Shao, Juntang
Zaro, Jennica L.
Shen, Wei-Chiang
Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
title Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
title_full Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
title_fullStr Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
title_full_unstemmed Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
title_short Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
title_sort proinsulin-transferrin fusion protein as a novel long-acting insulin analog for the inhibition of hepatic glucose production
topic Pharmacology and Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994961/
https://www.ncbi.nlm.nih.gov/pubmed/24353179
http://dx.doi.org/10.2337/db13-0973
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