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LAPS Insulin115: A novel ultra-long-acting basal insulin with a unique action profile.
Wronkowitz, Nina; Hartmann, Thorsten; Görgens, Sven Wolfgang; Dietze-Schroeder, Daniela; Indrakusuma, Ira; Choi, In Young; Park, Sung Hee; Lee, Young-Mi; Kwon, Se Chang; Kang, Yeonjoo; Hompesch, Marcus; Eckel, Jürgen.
Afiliación
  • Wronkowitz N; Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany.
  • Hartmann T; Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany.
  • Görgens SW; Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany.
  • Dietze-Schroeder D; Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany.
  • Indrakusuma I; Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany.
  • Choi IY; Hanmi Pharmaceutical, Co., Ltd., Seoul, South Korea.
  • Park SH; Hanmi Pharmaceutical, Co., Ltd., Seoul, South Korea.
  • Lee YM; Hanmi Pharmaceutical, Co., Ltd., Seoul, South Korea.
  • Kwon SC; Hanmi Pharmaceutical, Co., Ltd., Seoul, South Korea.
  • Kang Y; ProSciento, Inc., Chula Vista.
  • Hompesch M; ProSciento, Inc., Chula Vista.
  • Eckel J; Paul-Langerhans-Group, German Diabetes Centre, Düsseldorf, Germany.
Diabetes Obes Metab ; 19(12): 1722-1731, 2017 12.
Article en En | MEDLINE | ID: mdl-28497570
AIMS: To conduct a comprehensive pre-clinical study of the novel ultra-long acting insulin analogue LAPS Insulin115. METHODS: Pharmacokinetic/pharmacodynamic studies comparing LAPS Insulin115 with other basal insulins were conducted in genetically diabetic (db/db) mice. Insulin signalling in the major target organs was analysed using Western blot after single subcutaneous injection in wild-type male Wistar rats. Using in vitro assays we analysed transendothelial transport, insulin receptor (IR) interaction, and the mitogenic and metabolic properties of LAPS Insulin115. Furthermore, IR downregulation after long-term exposure to high concentrations of LAPS Insulin115 was analysed using an in vitro desensitization/resensitization model. RESULTS: The novel Fc-conjugated insulin derivative LAPS Insulin115 showed an extensively prolonged pharmacokinetic and pharmacodynamic profile in rodents. Despite its size of 59 kDa, LAPS Insulin115 passes the vascular endothelial barrier and induces insulin signalling in all major target tissues in rats. In vitro, LAPS Insulin115 showed a very slow onset of action because of its reduced IR affinity; however, after long-term stimulation it was equipotent in respect to its metabolic potency and showed no increased mitogenic action when compared with regular insulin. Remarkably, under conditions of chronic exposure, LAPS Insulin115 does not induce irreversible desensitization of target cells, which is probably attributable to much less prominent IR downregulation. CONCLUSION: Thus, LAPS Insulin115 exhibits a unique in vivo and in vitro profile and thereby represents an excellent candidate for a once-weekly insulin analogue.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fragmentos Fc de Inmunoglobulinas / Receptor de Insulina / Transducción de Señal / Drogas en Investigación / Regulación de la Expresión Génica / Insulina de Acción Prolongada / Hipoglucemiantes Idioma: En Revista: Diabetes Obes Metab Asunto de la revista: ENDOCRINOLOGIA / METABOLISMO Año: 2017 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fragmentos Fc de Inmunoglobulinas / Receptor de Insulina / Transducción de Señal / Drogas en Investigación / Regulación de la Expresión Génica / Insulina de Acción Prolongada / Hipoglucemiantes Idioma: En Revista: Diabetes Obes Metab Asunto de la revista: ENDOCRINOLOGIA / METABOLISMO Año: 2017 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido