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

Nature. 2000 Nov 23;408(6811):483-8. doi: 10.1038/35044106.


A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of beta 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 beta cells by autoimmune responses specific to beta cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic beta 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Base Sequence
  • Blood Glucose / metabolism
  • Cloning, Molecular
  • DNA, Complementary
  • DNA, Recombinant / genetics
  • DNA, Recombinant / metabolism
  • Dependovirus / genetics
  • Diabetes Mellitus, Experimental / therapy
  • Diabetes Mellitus, Type 1 / therapy*
  • Escherichia coli
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors
  • Glucose Tolerance Test
  • Half-Life
  • Hepatocytes / metabolism
  • Insulin / analogs & derivatives
  • Insulin / genetics*
  • Insulin / metabolism
  • Insulin Secretion
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Plasmids
  • Promoter Regions, Genetic
  • Rats
  • Rats, Sprague-Dawley


  • Blood Glucose
  • DNA, Complementary
  • DNA, Recombinant
  • Insulin