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. Roberts, W. Kenneth Ward

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)705-710
Number of pages6
JournalCurrent diabetes reports
Volume12
Issue number6
DOIs
StatePublished - Dec 1 2012

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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