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

  • Technological Development in Diabetes Therapies (S Russell, Section Editor)
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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.

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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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Authors and Affiliations

  1. Oregon Health and Science University (OHSU), 3181 SW Sam Jackson Park Road, OP05DC, Portland, OR, 97239, USA

    Melanie A. Jackson, Nicholas Caputo, Jessica R. Castle, Larry L. David, Charles T. Roberts Jr. & W. Kenneth Ward

  2. Legacy Health, 1225 NE 2nd Avenue, Portland, OR, USA

    Melanie A. Jackson, Nicholas Caputo, Jessica R. Castle, Larry L. David & Charles T. Roberts Jr.

Authors
  1. Melanie A. Jackson
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  2. Nicholas Caputo
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  3. Jessica R. Castle
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  4. Larry L. David
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  5. Charles T. Roberts Jr.
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  6. W. Kenneth Ward
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Correspondence to W. Kenneth Ward.

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Jackson, M.A., Caputo, N., Castle, J.R. et al. Stable Liquid Glucagon Formulations for Rescue Treatment and Bi-Hormonal Closed-Loop Pancreas. Curr Diab Rep 12, 705–710 (2012). https://doi.org/10.1007/s11892-012-0320-5

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  • DOI: https://doi.org/10.1007/s11892-012-0320-5

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