Submitted on September 16, 2008
Revised on January 30, 2009
Accepted on January 30, 2009
Engineered Glucagon-Like Peptide-1-Producing Hepatocytes Lower Plasma Glucose Levels in Mice
Michael J Riedel1, Corrina WK Lee1, and Timothy J Kieffer1*
1 University of British Columbia
* To whom correspondence should be addressed. E-mail: tim.kieffer{at}ubc.ca.
Glucagon-like peptide (GLP)-1 is an incretin hormone with well-characterized anti-diabetic properties including glucose-dependent stimulation of insulin secretion and enhancement of 
-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 neural 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 N-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 be 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.
