title: Proinsulin-transferrin fusion protein as a novel long-acting insulin analog for the inhibition of hepatic glucose production.
abstract: 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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Juntang
authors.initials: J
authors.lastname: Shao
authors.forename: Jennica L
authors.initials: JL
authors.lastname: Zaro
authors.forename: Wei-Chiang
authors.initials: WC
authors.lastname: Shen
mesh_terms: D045744:Cell Line, Tumor; D004338:Drug Combinations; D006801:Humans; D049528:Insulin, Long-Acting / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D011384:Proinsulin / Q000493:pharmacokinetics / Q000494:pharmacology*; D014168:Transferrin / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004338:Drug Combinations; D049528:Insulin, Long-Acting; D014168:Transferrin; D011384:Proinsulin