Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Jung Seok Lee, Patrick Han, Rabib Chaudhury, Shihan Khan, Sean Bickerton, Michael D. McHugh, Hyun Bong Park, Alyssa L. Siefert, Gerald Rea, José M. Carballido, David A. Horwitz, Jason Criscione, Karlo Perica, Robert Samstein, Ragy Rageb, Dongin Kim, Tarek M. Fahmy

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)983-997
Number of pages15
JournalNature Biomedical Engineering
Volume5
Issue number9
DOIs
StatePublished - Sep 2021
Externally publishedYes

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