Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate

The Ability to Activate the Glucagon-Like Peptide 1 Receptor In Vivo

  1. Jung-Guk Kim1,
  2. Laurie L. Baggio1,
  3. Dominique P. Bridon2,
  4. Jean-Paul Castaigne2,
  5. Martin F. Robitaille2,
  6. Lucie Jetté2,
  7. Corinne Benquet2 and
  8. Daniel J. Drucker1
  1. 1Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Ontario
  2. 2Conjuchem, Montreal, Quebec

    Abstract

    The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP-1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R. CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R−/− mice. Basal glucose and glycemic excursion following glucose challenge remained significantly reduced 10–12 h following a single injection of CJC-1131. Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period. Levels of random fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and remained significantly lower even 1 week following discontinuation of CJC-1131 administration. CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1 mimics the action of native GLP-1 and represents a new approach for prolonged activation of GLP-1R signaling.

    Footnotes

    • Address correspondence and reprint requests to Dr. Daniel J Drucker, 200 Elizabeth St., MBRW-4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca.

      Received for publication 16 July 2002 and accepted in revised form 6 November 2002.

      AUC, area under the curve; CHO, Chinese hamster ovary; DAC, drug affinity complex; DPP-IV, dipeptidyl peptidase-IV; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; HSA, human serum albumin.

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