Current Diabetes Reports

, Volume 12, Issue 6, pp 705–710 | Cite as

Stable Liquid Glucagon Formulations for Rescue Treatment and Bi-Hormonal Closed-Loop Pancreas

  • Melanie A. Jackson
  • Nicholas Caputo
  • Jessica R. Castle
  • Larry L. David
  • Charles T. RobertsJr.
  • W. Kenneth Ward
Technological Development in Diabetes Therapies (S Russell, Section Editor)

Abstract

Small doses of glucagon given subcutaneously in the research setting by an automated system prevent most cases of hypoglycemia in persons with diabetes. However, glucagon is very unstable and cannot be kept in a portable pump. Glucagon rapidly forms amyloid fibrils, even within the first day after reconstitution. Aggregation eventually leads to insoluble gels, which occlude pump catheters. Fibrillation occurs rapidly at acid pH, but is absent or minimal at alkaline pH values of ~10. Glucagon also degrades over time; this problem is greater at alkaline pH. Several studies suggest that its primary degradative pathway is deamidation, which results in a conversion of asparagine to aspartic acid. A cell-based assay for glucagon bioactivity that assesses glucagon receptor (GluR) activation can screen promising glucagon formulations. However, mammalian hepatocytes are usually problematic as they can lose GluR expression during culture. Assays for cyclic AMP (cAMP) or its downstream effector, protein kinase A (PKA), in engineered cell systems, are more reliable and suitable for inexpensive, high-throughput assessment of bioactivity.

Keywords

Glucagon Cytotoxicity Amyloid Diabetes Assay Rescue treatment Bi-hormonal closed-loop pancreas 

Notes

Acknowledgments

This work was financially supported in part by grants from Juvenile Diabetes Research Foundation (#17-2012-15), the Legacy Good Samaritan Foundation, and by NIH (NCRR,ORIP) grant # P51OD011092.

Disclosure

Conflicts of interest: MA Jackson: none N Caputo: has received grant support from the Juvenile Diabetes Research Foundation; and Novo Nordisk provided glucagon for research purposes as an in kind donation; JR Castle: has received grant support from the Juvenile Diabetes Research Foundation; and is on the Speaker's Bureau for Amylin; LL David: none; CT Roberts Jr: has received grant support from the Juvenile Diabetes Research Foundation; WK Ward: has received grant support from the Juvenile Diabetes Research Foundation; has received support for travel to meetings for the study or otherwise from the Juvenile Diabetes Research Foundation; Novo Nordisk provided glucagon for research purposes as an in kind donation; is on the scientific advisory board of Xerix Pharmaceuticals; some of the authors filed patents regarding methods of chemically stabilizing glucagon.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Melanie A. Jackson
    • 1
    • 2
  • Nicholas Caputo
    • 1
    • 2
  • Jessica R. Castle
    • 1
    • 2
  • Larry L. David
    • 1
    • 2
  • Charles T. RobertsJr.
    • 1
    • 2
  • W. Kenneth Ward
    • 1
  1. 1.Oregon Health and Science University (OHSU)PortlandUSA
  2. 2.Legacy HealthPortlandUSA

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