Long-term reversal of diabetes by the injection of immunoprotected islets

Patrick Soon-Shiono, Edward C Feldman, Richard W Nelson, Roswitha Heintz, Qiang Yao, Zhiwen Yao, Tianli Zheng, Noma Merideth, Gudmund Skjak-Braek, Terje Espevik, Olav Smidsrod, Paul Sandford

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

The intraperitoneal injection of insulin-producing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Previous attempts to demonstrate this technology in large animals have failed, preventing application in humans. We have determined that key factors responsible for these past failures include cytokine (interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibreblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontaneous diabetic dog model by the intraperitoneal injection of encapsulated canine islet allografts. Euglycemia, independent of any exogenous insulin requirement, was noted for up to 172 days. Graft survival, evidenced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immunoprotective nature of this capsule formulation. The finding that intraperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (>1 year) maintenance of glycemic control, without the need for lifelong immunosuppression, may have significant implications for the future therapy of type I diabetes in humans.

Original languageEnglish (US)
Pages (from-to)5843-5847
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number12
StatePublished - Jun 15 1993

Fingerprint

Intraperitoneal Injections
Capsules
Injections
Immunosuppression
Insulin
Minimally Invasive Surgical Procedures
C-Peptide
Peritoneal Cavity
Graft Survival
Type 1 Diabetes Mellitus
Interleukin-1
Allografts
Canidae
Interleukin-6
Tumor Necrosis Factor-alpha
Maintenance
Dogs
Cytokines
Technology
Amino Acids

Keywords

  • Alginate microcapsule
  • Dogs
  • Islet allograft

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Long-term reversal of diabetes by the injection of immunoprotected islets. / Soon-Shiono, Patrick; Feldman, Edward C; Nelson, Richard W; Heintz, Roswitha; Yao, Qiang; Yao, Zhiwen; Zheng, Tianli; Merideth, Noma; Skjak-Braek, Gudmund; Espevik, Terje; Smidsrod, Olav; Sandford, Paul.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 90, No. 12, 15.06.1993, p. 5843-5847.

Research output: Contribution to journalArticle

Soon-Shiono, P, Feldman, EC, Nelson, RW, Heintz, R, Yao, Q, Yao, Z, Zheng, T, Merideth, N, Skjak-Braek, G, Espevik, T, Smidsrod, O & Sandford, P 1993, 'Long-term reversal of diabetes by the injection of immunoprotected islets', Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 12, pp. 5843-5847.
Soon-Shiono, Patrick ; Feldman, Edward C ; Nelson, Richard W ; Heintz, Roswitha ; Yao, Qiang ; Yao, Zhiwen ; Zheng, Tianli ; Merideth, Noma ; Skjak-Braek, Gudmund ; Espevik, Terje ; Smidsrod, Olav ; Sandford, Paul. / Long-term reversal of diabetes by the injection of immunoprotected islets. In: Proceedings of the National Academy of Sciences of the United States of America. 1993 ; Vol. 90, No. 12. pp. 5843-5847.
@article{37098ef31c044c888f51ce14a467ac5a,
title = "Long-term reversal of diabetes by the injection of immunoprotected islets",
abstract = "The intraperitoneal injection of insulin-producing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Previous attempts to demonstrate this technology in large animals have failed, preventing application in humans. We have determined that key factors responsible for these past failures include cytokine (interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibreblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontaneous diabetic dog model by the intraperitoneal injection of encapsulated canine islet allografts. Euglycemia, independent of any exogenous insulin requirement, was noted for up to 172 days. Graft survival, evidenced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immunoprotective nature of this capsule formulation. The finding that intraperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (>1 year) maintenance of glycemic control, without the need for lifelong immunosuppression, may have significant implications for the future therapy of type I diabetes in humans.",
keywords = "Alginate microcapsule, Dogs, Islet allograft",
author = "Patrick Soon-Shiono and Feldman, {Edward C} and Nelson, {Richard W} and Roswitha Heintz and Qiang Yao and Zhiwen Yao and Tianli Zheng and Noma Merideth and Gudmund Skjak-Braek and Terje Espevik and Olav Smidsrod and Paul Sandford",
year = "1993",
month = "6",
day = "15",
language = "English (US)",
volume = "90",
pages = "5843--5847",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "12",

}

TY - JOUR

T1 - Long-term reversal of diabetes by the injection of immunoprotected islets

AU - Soon-Shiono, Patrick

AU - Feldman, Edward C

AU - Nelson, Richard W

AU - Heintz, Roswitha

AU - Yao, Qiang

AU - Yao, Zhiwen

AU - Zheng, Tianli

AU - Merideth, Noma

AU - Skjak-Braek, Gudmund

AU - Espevik, Terje

AU - Smidsrod, Olav

AU - Sandford, Paul

PY - 1993/6/15

Y1 - 1993/6/15

N2 - The intraperitoneal injection of insulin-producing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Previous attempts to demonstrate this technology in large animals have failed, preventing application in humans. We have determined that key factors responsible for these past failures include cytokine (interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibreblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontaneous diabetic dog model by the intraperitoneal injection of encapsulated canine islet allografts. Euglycemia, independent of any exogenous insulin requirement, was noted for up to 172 days. Graft survival, evidenced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immunoprotective nature of this capsule formulation. The finding that intraperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (>1 year) maintenance of glycemic control, without the need for lifelong immunosuppression, may have significant implications for the future therapy of type I diabetes in humans.

AB - The intraperitoneal injection of insulin-producing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Previous attempts to demonstrate this technology in large animals have failed, preventing application in humans. We have determined that key factors responsible for these past failures include cytokine (interleukins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibreblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontaneous diabetic dog model by the intraperitoneal injection of encapsulated canine islet allografts. Euglycemia, independent of any exogenous insulin requirement, was noted for up to 172 days. Graft survival, evidenced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immunoprotective nature of this capsule formulation. The finding that intraperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (>1 year) maintenance of glycemic control, without the need for lifelong immunosuppression, may have significant implications for the future therapy of type I diabetes in humans.

KW - Alginate microcapsule

KW - Dogs

KW - Islet allograft

UR - http://www.scopus.com/inward/record.url?scp=0027230803&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027230803&partnerID=8YFLogxK

M3 - Article

C2 - 8516335

AN - SCOPUS:0027230803

VL - 90

SP - 5843

EP - 5847

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 12

ER -