Engineered glucagon-like peptide-1-producing hepatocytes lower plasma glucose levels in mice.
Glucagon-like peptide (GLP)-1 is an incretin hormone with well-characterized antidiabetic properties, including glucose-dependent stimulation of insulin secretion and enhancement of beta-cell mass. GLP-1 agonists have recently been developed and are now in clinical use for the treatment of type 2 diabetes. Rapid degradation of GLP-1 by enzymes including dipeptidyl-peptidase (DPP)-IV and neutral endopeptidase (NEP) 24.11, along with renal clearance, contribute to a short biological half-life, necessitating frequent injections to maintain therapeutic efficacy. Gene therapy may represent a promising alternative approach for achieving long-term increases in endogenous release of GLP-1. We have developed a novel strategy for glucose-regulated production of GLP-1 in hepatocytes by expressing a DPP-IV-resistant GLP-1 peptide in hepatocytes under control of the liver-type pyruvate kinase promoter. Adenoviral delivery of this construct to hepatocytes in vitro resulted in production and secretion of bioactive GLP-1 as measured by a luciferase-based bioassay developed to detect the NH2-terminally modified GLP-1 peptide engineered for this study. Transplantation of encapsulated hepatocytes into CD-1 mice resulted in an increase in plasma GLP-1 levels that was accompanied by a significant reduction in fasting plasma glucose levels. The results from this study demonstrate that a gene therapy approach designed to induce GLP-1 production in hepatocytes may represent a novel strategy for long-term secretion of bioactive GLP-1 for the treatment of type 2 diabetes.
Riedel
Michael J
MJ
Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Lee
Corinna Wai Kwan
CW
Kieffer
Timothy J
TJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001681:Biological Assay / Q000379:methods; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism / Q000628:therapy* / Q000662:veterinary; D015536:Down-Regulation; D005818:Genetic Engineering / Q000379:methods; D052216:Glucagon-Like Peptide 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation*; D006801:Humans; D008297:Male; D051379:Mice; D014161:Transduction, Genetic / Q000379:methods
D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D005947:Glucose