Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes

Ming Yu; Divyansh Agarwal; Laxminarayana Korutla; Catherine L. May; Wei Wang; Negin Noorchashm Griffith; Bernhard J. Hering; Klaus H. Kaestner; Omaida C. Velazquez; James F. Markmann; Prashanth Vallabhajosyula; Chengyang Liu; Ali Naji

doi:10.1038/s42255-020-0269-7

Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes

Ming Yu, Divyansh Agarwal, Laxminarayana Korutla, Catherine L. May, Wei Wang, Negin Noorchashm Griffith, Bernhard J. Hering, Klaus H. Kaestner, Omaida C. Velazquez, James F. Markmann, Prashanth Vallabhajosyula, Chengyang Liu, Ali Naji

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Abstract

The intrahepatic milieu is inhospitable to intraportal islet allografts^1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.

Original language	English (US)
Pages (from-to)	1013-1020
Number of pages	8
Journal	Nature Metabolism
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s42255-020-0269-7
State	Published - Oct 1 2020

Bibliographical note

Funding Information:
We thank S. Rostami, B. Koeberlein and G. Quinn for their valuable assistance in data collection and development of animal models. We thank Y. J. Wang for assistance with the islet β-cell BrdU staining experiments. We also acknowledge the support of J. Schug, Technical Director of the Next-Generation Sequencing Core at the University of Pennsylvania, for exosome sequencing analysis. We thank members of the Pancreatic Islet Isolation Team at the University of Pennsylvania (Y. Li, Z. Min and X. Zuo). D.A. thanks the Blavatnik Family Foundation for the Graduate Student Fellowship he received during his MD/PhD training. We also thank the National Institutes of Health for award nos. NIH/ NIDDK DK070430, NIH/NIAID AI-102430 and NIH/NIDDK UC4–112217 (HPAP), and the NIDDK IIDP for the grant (Beckman Research Center, no. 10028044) awarded to A.N.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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Yu, M., Agarwal, D., Korutla, L., May, C. L., Wang, W., Griffith, N. N., Hering, B. J., Kaestner, K. H., Velazquez, O. C., Markmann, J. F., Vallabhajosyula, P., Liu, C., & Naji, A. (2020). Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes. Nature Metabolism, 2(10), 1013-1020. https://doi.org/10.1038/s42255-020-0269-7

Yu, M, Agarwal, D, Korutla, L, May, CL, Wang, W, Griffith, NN, Hering, BJ, Kaestner, KH, Velazquez, OC, Markmann, JF, Vallabhajosyula, P, Liu, C & Naji, A 2020, 'Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes', Nature Metabolism, vol. 2, no. 10, pp. 1013-1020. https://doi.org/10.1038/s42255-020-0269-7

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abstract = "The intrahepatic milieu is inhospitable to intraportal islet allografts1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.",

author = "Ming Yu and Divyansh Agarwal and Laxminarayana Korutla and May, {Catherine L.} and Wei Wang and Griffith, {Negin Noorchashm} and Hering, {Bernhard J.} and Kaestner, {Klaus H.} and Velazquez, {Omaida C.} and Markmann, {James F.} and Prashanth Vallabhajosyula and Chengyang Liu and Ali Naji",

note = "Funding Information: We thank S. Rostami, B. Koeberlein and G. Quinn for their valuable assistance in data collection and development of animal models. We thank Y. J. Wang for assistance with the islet β-cell BrdU staining experiments. We also acknowledge the support of J. Schug, Technical Director of the Next-Generation Sequencing Core at the University of Pennsylvania, for exosome sequencing analysis. We thank members of the Pancreatic Islet Isolation Team at the University of Pennsylvania (Y. Li, Z. Min and X. Zuo). D.A. thanks the Blavatnik Family Foundation for the Graduate Student Fellowship he received during his MD/PhD training. We also thank the National Institutes of Health for award nos. NIH/ NIDDK DK070430, NIH/NIAID AI-102430 and NIH/NIDDK UC4–112217 (HPAP), and the NIDDK IIDP for the grant (Beckman Research Center, no. 10028044) awarded to A.N. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

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T1 - Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes

AU - Yu, Ming

AU - Agarwal, Divyansh

AU - Korutla, Laxminarayana

AU - May, Catherine L.

AU - Wang, Wei

AU - Griffith, Negin Noorchashm

AU - Hering, Bernhard J.

AU - Kaestner, Klaus H.

AU - Velazquez, Omaida C.

AU - Markmann, James F.

AU - Vallabhajosyula, Prashanth

AU - Liu, Chengyang

AU - Naji, Ali

N1 - Funding Information: We thank S. Rostami, B. Koeberlein and G. Quinn for their valuable assistance in data collection and development of animal models. We thank Y. J. Wang for assistance with the islet β-cell BrdU staining experiments. We also acknowledge the support of J. Schug, Technical Director of the Next-Generation Sequencing Core at the University of Pennsylvania, for exosome sequencing analysis. We thank members of the Pancreatic Islet Isolation Team at the University of Pennsylvania (Y. Li, Z. Min and X. Zuo). D.A. thanks the Blavatnik Family Foundation for the Graduate Student Fellowship he received during his MD/PhD training. We also thank the National Institutes of Health for award nos. NIH/ NIDDK DK070430, NIH/NIAID AI-102430 and NIH/NIDDK UC4–112217 (HPAP), and the NIDDK IIDP for the grant (Beckman Research Center, no. 10028044) awarded to A.N. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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N2 - The intrahepatic milieu is inhospitable to intraportal islet allografts1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.

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Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes

Abstract

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