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Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue

A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from th... Full description

Journal Title: Nature (London) 2000-11-23, Vol.408 (6811), p.483-488
Main Author: Lee, Hyun Chul
Other Authors: Kim, Su-Jin , Kim, Kyung-Sup , Shin, Hang-Cheol , Yoon, Ji-Won
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: Nature Publishing
ID: ISSN: 0028-0836
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recordid: cdi_proquest_miscellaneous_743419631
title: Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue
format: Article
creator:
  • Lee, Hyun Chul
  • Kim, Su-Jin
  • Kim, Kyung-Sup
  • Shin, Hang-Cheol
  • Yoon, Ji-Won
subjects:
  • Adeno-associated virus
  • Animals
  • Base Sequence
  • Biological and medical sciences
  • Blood Glucose - metabolism
  • Cloning, Molecular
  • Dependovirus - genetics
  • Diabetes Mellitus, Experimental - therapy
  • Diabetes Mellitus, Type 1 - therapy
  • DNA, Complementary
  • DNA, Recombinant - genetics
  • DNA, Recombinant - metabolism
  • Escherichia coli
  • Gene Expression
  • Genetic Therapy
  • Genetic Vectors
  • Glucose Tolerance Test
  • Half-Life
  • Hepatocytes - metabolism
  • Hormones. Endocrine system
  • Insulin - analogs & derivatives
  • Insulin - genetics
  • Insulin - metabolism
  • Insulin Secretion
  • Liver - metabolism
  • Male
  • Medical sciences
  • Mice
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Pharmacology. Drug treatments
  • Plasmids
  • Promoter Regions, Genetic
  • Rats
  • Rats, Sprague-Dawley
ispartof: Nature (London), 2000-11-23, Vol.408 (6811), p.483-488
description: A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
url: Link


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descriptionA cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.
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subjectAdeno-associated virus ; Animals ; Base Sequence ; Biological and medical sciences ; Blood Glucose - metabolism ; Cloning, Molecular ; Dependovirus - genetics ; Diabetes Mellitus, Experimental - therapy ; Diabetes Mellitus, Type 1 - therapy ; DNA, Complementary ; DNA, Recombinant - genetics ; DNA, Recombinant - metabolism ; Escherichia coli ; Gene Expression ; Genetic Therapy ; Genetic Vectors ; Glucose Tolerance Test ; Half-Life ; Hepatocytes - metabolism ; Hormones. Endocrine system ; Insulin - analogs & derivatives ; Insulin - genetics ; Insulin - metabolism ; Insulin Secretion ; Liver - metabolism ; Male ; Medical sciences ; Mice ; Mice, Inbred NOD ; Molecular Sequence Data ; Pharmacology. Drug treatments ; Plasmids ; Promoter Regions, Genetic ; Rats ; Rats, Sprague-Dawley
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descriptionA cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.
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4Blood Glucose - metabolism
5Cloning, Molecular
6Dependovirus - genetics
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8Diabetes Mellitus, Type 1 - therapy
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abstractA cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.
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