Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

Sai Bo Bo Tun; Minni Chua; Riasat Hasan; Martin Köhler; Xiaofeng Zheng; Yusuf Ali; Midhat H. Abdulreda; Lisa Juntti-Berggren; Veluchamy A. Barathi; Per Olof Berggren

doi:10.1177/0963689720913256

Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

Sai Bo Bo Tun, Minni Chua, Riasat Hasan, Martin Köhler, Xiaofeng Zheng, Yusuf Ali, Midhat H. Abdulreda, Lisa Juntti-Berggren, Veluchamy A. Barathi, Per Olof Berggren

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Abstract

Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A_1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.

Original language	English
Pages (from-to)	1-9
Number of pages	9
Journal	Cell Transplantation
Volume	29
DOIs	https://doi.org/10.1177/0963689720913256
Publication status	Published (in print/issue) - 7 Apr 2020

Bibliographical note

Funding Information:
We thank Dr. Bryan Ogden and the veterinary team from SingHealth Experimental Medicine Centre (SEMC) for the husbandry care and handling of the animals. We appreciate the advice and input of Dr. Hla Myat Htoon from Singapore Eye Research Institute (SERI) on the statistical analysis. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant M4230003 (to P-OB), Lee Kong Chian School of Medicine, Nanyang Technological University Bridging Assistant Grants 4, the Lee Foundation Grant 2015 granted by SingHealth Transplant. VAB was supported by NMRC/CG-INCEPTOR/Pre-Clinical Core Platform/2017_SERI. P-OB was also supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the Scandia Insurance Company Limited, and the Diabetes Research and Wellness Foundation. Article processing charge was supported by National Medical Research Council (NMRC/CG/C010A-PreClinical/2017) of Singapore.

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant M4230003 (to P-OB), Lee Kong Chian School of Medicine, Nanyang Technological University Bridging Assistant Grants 4, the Lee Foundation Grant 2015 granted by SingHealth Transplant. VAB was supported by NMRC/CG-INCEPTOR/Pre-Clinical Core Platform/2017_SERI. P-OB was also supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the Scandia Insurance Company Limited, and the Diabetes Research and Wellness Foundation. Article processing charge was supported by National Medical Research Council (NMRC/CG/C010A-PreClinical/2017) of Singapore.

Publisher Copyright:
© The Author(s) 2020.

Keywords

anterior chamber of the eye
diet-induced type-2 diabetes
intraocular transplant
islet transplantation
nonhuman primates

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Tun, S. B. B., Chua, M., Hasan, R., Köhler, M., Zheng, X., Ali, Y., Abdulreda, M. H., Juntti-Berggren, L., Barathi, V. A., & Berggren, P. O. (2020). Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate. Cell Transplantation, 29, 1-9. https://doi.org/10.1177/0963689720913256

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title = "Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate",

abstract = "Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.",

keywords = "anterior chamber of the eye, diet-induced type-2 diabetes, intraocular transplant, islet transplantation, nonhuman primates",

author = "Tun, {Sai Bo Bo} and Minni Chua and Riasat Hasan and Martin K{\"o}hler and Xiaofeng Zheng and Yusuf Ali and Abdulreda, {Midhat H.} and Lisa Juntti-Berggren and Barathi, {Veluchamy A.} and Berggren, {Per Olof}",

note = "Funding Information: We thank Dr. Bryan Ogden and the veterinary team from SingHealth Experimental Medicine Centre (SEMC) for the husbandry care and handling of the animals. We appreciate the advice and input of Dr. Hla Myat Htoon from Singapore Eye Research Institute (SERI) on the statistical analysis. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant M4230003 (to P-OB), Lee Kong Chian School of Medicine, Nanyang Technological University Bridging Assistant Grants 4, the Lee Foundation Grant 2015 granted by SingHealth Transplant. VAB was supported by NMRC/CG-INCEPTOR/Pre-Clinical Core Platform/2017_SERI. P-OB was also supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the Scandia Insurance Company Limited, and the Diabetes Research and Wellness Foundation. Article processing charge was supported by National Medical Research Council (NMRC/CG/C010A-PreClinical/2017) of Singapore. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant M4230003 (to P-OB), Lee Kong Chian School of Medicine, Nanyang Technological University Bridging Assistant Grants 4, the Lee Foundation Grant 2015 granted by SingHealth Transplant. VAB was supported by NMRC/CG-INCEPTOR/Pre-Clinical Core Platform/2017_SERI. P-OB was also supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the Scandia Insurance Company Limited, and the Diabetes Research and Wellness Foundation. Article processing charge was supported by National Medical Research Council (NMRC/CG/C010A-PreClinical/2017) of Singapore. Publisher Copyright: {\textcopyright} The Author(s) 2020.",

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day = "7",

doi = "10.1177/0963689720913256",

language = "English",

volume = "29",

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Tun, SBB, Chua, M, Hasan, R, Köhler, M, Zheng, X, Ali, Y, Abdulreda, MH, Juntti-Berggren, L, Barathi, VA & Berggren, PO 2020, 'Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate', Cell Transplantation, vol. 29, pp. 1-9. https://doi.org/10.1177/0963689720913256

TY - JOUR

T1 - Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

AU - Tun, Sai Bo Bo

AU - Chua, Minni

AU - Hasan, Riasat

AU - Köhler, Martin

AU - Zheng, Xiaofeng

AU - Ali, Yusuf

AU - Abdulreda, Midhat H.

AU - Juntti-Berggren, Lisa

AU - Barathi, Veluchamy A.

AU - Berggren, Per Olof

N1 - Funding Information: We thank Dr. Bryan Ogden and the veterinary team from SingHealth Experimental Medicine Centre (SEMC) for the husbandry care and handling of the animals. We appreciate the advice and input of Dr. Hla Myat Htoon from Singapore Eye Research Institute (SERI) on the statistical analysis. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant M4230003 (to P-OB), Lee Kong Chian School of Medicine, Nanyang Technological University Bridging Assistant Grants 4, the Lee Foundation Grant 2015 granted by SingHealth Transplant. VAB was supported by NMRC/CG-INCEPTOR/Pre-Clinical Core Platform/2017_SERI. P-OB was also supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the Scandia Insurance Company Limited, and the Diabetes Research and Wellness Foundation. Article processing charge was supported by National Medical Research Council (NMRC/CG/C010A-PreClinical/2017) of Singapore. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant M4230003 (to P-OB), Lee Kong Chian School of Medicine, Nanyang Technological University Bridging Assistant Grants 4, the Lee Foundation Grant 2015 granted by SingHealth Transplant. VAB was supported by NMRC/CG-INCEPTOR/Pre-Clinical Core Platform/2017_SERI. P-OB was also supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Stichting af Jochnick Foundation, the Scandia Insurance Company Limited, and the Diabetes Research and Wellness Foundation. Article processing charge was supported by National Medical Research Council (NMRC/CG/C010A-PreClinical/2017) of Singapore. Publisher Copyright: © The Author(s) 2020.

PY - 2020/4/7

Y1 - 2020/4/7

N2 - Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.

AB - Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.

KW - anterior chamber of the eye

KW - diet-induced type-2 diabetes

KW - intraocular transplant

KW - islet transplantation

KW - nonhuman primates

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SN - 0963-6897

ER -

Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

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Bibliographical note

Keywords

UN SDGs

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