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 cucurbituril-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.
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All data supporting the results in this study are available within the article and its Supplementary information. The broad range of raw datasets acquired and analysed (or any subsets thereof), which would require contextual metadata for reuse, are available from the corresponding author on reasonable request.
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This work was funded in part by a NIDDK R01 (the National Institutes of Health grant no. R01DK119254), a Pilot and Feasibility funding from the Stanford Diabetes Research Center (NIH grant no. P30DK116074) and the Stanford Child Health Research Institute, as well as a Research Starter Grant from the PhRMA Foundation. C.L.M. was supported by the NSERC Postgraduate Scholarship and the Stanford Bio-X Bowes Graduate Student Fellowship. A.A.A.S. was funded by grant no. NNF18OC0030896 from the Novo Nordisk Foundation and the Stanford Bio-X Program, as well as by the Danish Council of Independent Research (grant no. DFF5054-00215). The authors thank the Stanford Animal Diagnostic Lab and the Veterinary Service Centre staff for their technical assistance.
E.A.A., B.A.B., D.M.M., C.L.M. and G.A.R. are inventors on a patent filing (provisional application no. 62/804,357) describing the work reported in this manuscript.
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Maikawa, C.L., Smith, A.A.A., Zou, L. et al. A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs. Nat Biomed Eng 4, 507–517 (2020). https://doi.org/10.1038/s41551-020-0555-4
Nature Biomedical Engineering (2020)