Trends in Molecular Medicine
ReviewRecent advances in insulin gene therapy for type 1 diabetes
Section snippets
Insulin gene transfer systems
The transfer of defined genetic material to specific target cells is an essential component of gene therapy. It can be accomplished using nonviral or viral vectors.
Glucose-responsive insulin production
Pancreatic β cells contain unique features that allow the regulation of insulin synthesis and secretion in response to physiological glucose concentrations. It is not easy to reconstruct this regulated system outside of the pancreatic β cells, as several cellular structures and proteins are required for the secretion of insulin in response to changes in extracellular glucose concentrations, including cis- and trans-activating factors, glucose transporter (Glut) 2, glucokinase (GK) and
Production of biologically active insulin
Insulin is a polypeptide hormone that consists of two polypeptide chains, A and B, linked by two interchain and one intrachain disulfide bond. Insulin is synthesized as a single-chain precursor, preproinsulin. Cleavage of a 24-residue N-terminal ‘signal sequence’ from preproinsulin yields proinsulin, an 81-residue polypeptide consisting of A- and B-chains separated by a connecting (C)-peptide. Proinsulin is packaged into storage secretory granules where it undergoes folding and disulfide bond
Target cell for insulin gene expression
Pancreatic β cells in type 1 diabetic patients are the target of autoimmune attack, requiring that subjects undergoing islet cell transplantation be maintained on immunosuppressant drugs, which have adverse side-effects in some cases. A distinct advantage of insulin gene therapy is that non-β cells that are genetically engineered to produce insulin should not be recognized by these autoimmune responses [48]. However, such somatic insulin gene therapy is hampered by the complexity of insulin
Concluding remarks
Insulin gene therapy has been investigated as a possible method for the permanent treatment of type 1 diabetes (Fig. 4). With advances in molecular biological and recombinant DNA techniques, and our increased understanding of the biochemical mechanisms of glucose-regulated insulin secretion from β cells, significant progress has been made. Although glucose-responsive expression of transgenic insulin has been achieved, none of the insulin gene therapy trials to date was able to mimic normal β
Acknowledgements
We thank A.L. Kyle for editorial assistance. J-W.Y. is a Heritage Medical Scientist Awardee of the Alberta Heritage Foundation for Medical Research and holds a Canada Research Chair in Diabetes. This work was supported by the Canadian Institutes of Health Research and the National Institutes of Health.
References (62)
- et al.
Insulin-dependent diabetes mellitus
- et al.
Towards gene therapy of diabetes mellitus
Mol. Med. Today
(1999) Toward engineering skeletal muscle to release peptide hormone from the human pre-proinsulin gene
Transplant. Proc.
(1998)- et al.
Development of lentiviral vectors for gene therapy for human diseases
Blood
(2000) - et al.
Expanded-capacity adenoviral vectors – the helper-dependent vectors
Mol. Med. Today
(1999) - et al.
Adeno-associated virus vectors and hematology
Blood
(1999) Adeno-associated virus: integration at a specific chromosomal locus
Curr. Opin. Genet. Dev.
(1993)Respective roles of glucose, fructose, and insulin in the regulation of the liver-specific pyruvate kinase gene promoter
J. Biol. Chem.
(1994)Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription
J. Biol. Chem.
(1995)Exploration of a liver-specific, glucose/insulin-responsive promoter in transgenic mice
J. Biol. Chem.
(1993)