A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs

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  • Caitlin L. Maikawa, Stanford University
  • ,
  • Anton A.A. Smith, Stanford University
  • ,
  • Lei Zou, University of Notre Dame
  • ,
  • Gillie A. Roth, Stanford University
  • ,
  • Emily C. Gale, Stanford University
  • ,
  • Lyndsay M. Stapleton, Stanford University
  • ,
  • Sam W. Baker, Stanford University
  • ,
  • Joseph L. Mann, Stanford University
  • ,
  • Anthony C. Yu, Stanford University
  • ,
  • Santiago Correa, Stanford University
  • ,
  • Abigail K. Grosskopf, Stanford University
  • ,
  • Celine S. Liong, Stanford University
  • ,
  • Catherine M. Meis, Stanford University
  • ,
  • Doreen Chan, Stanford University
  • ,
  • Megan Troxell, Stanford University
  • ,
  • David M. Maahs, Stanford University
  • ,
  • Bruce A. Buckingham, Stanford University
  • ,
  • Matthew J. Webber, University of Notre Dame
  • ,
  • Eric A. Appel, Stanford University

Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.

Original languageEnglish
JournalNature Biomedical Engineering
Volume4
Issue5
Pages (from-to)507-517
Number of pages11
DOIs
Publication statusPublished - May 2020

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