한빛사논문
Jung Seok Lee 1, Patrick Han 2, Rabib Chaudhury2, Shihan Khan1, Sean Bickerton 1, Michael D. McHugh1, Hyun Bong Park3, Alyssa L. Siefert1, Gerald Rea4, José M. Carballido 5, David A. Horwitz6, Jason Criscione1, Karlo Perica1, Robert Samstein1, Ragy Rageb1, Dongin Kim1,7 and Tarek M. Fahmy 1,2,8 ,*
1Department of Biomedical Engineering, Yale University, New Haven, CT, USA. 2Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA. 3Department of Chemistry, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA. 4Toralgen Inc., Indianapolis, IN, USA. 5Novartis Institutes for BioMedical Research, Basel, Switzerland. 6Medicine and Molecular Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 7Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 8Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA.
*Corresponding author.
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.
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