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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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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 |
Sumario: | 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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