Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.
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The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures are provided with this paper. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding author on reasonable request.
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We thank K. Herold and R. Flavell for helpful discussions and input regarding the diabetic animal models and future applications of the technology; Pfizer Autoimmune Inc. (Cambridge, MA) for partial funding of this work; the JDRF for an early pilot grant that motivated the work; the Yale Autoimmune Center of Excellence pilot grant to T.M.F. (director K. Herold). This work was partially supported by NIH grants 1R01CA199004 and 1R01CA026412 to T.M.F and Toralgen Inc., by Novartis Institutes for BioMedical Research and by the Yale Institute for Nanoscience and Quantum Engineering to T.M.F.
T.M.F is a founder and major shareholder of Toralgen Inc., which focuses on the use of the system described in this work for different disease states, including autoimmunity and specifically type 1 and type 2 diabetes.
Peer review information Nature Biomedical Engineering thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.
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Lee, J.S., Han, P., Chaudhury, R. et al. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin. Nat Biomed Eng 5, 983–997 (2021). https://doi.org/10.1038/s41551-021-00791-0
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