title: Adenoviral vector-mediated glucagon-like peptide 1 gene therapy improves glucose homeostasis in Zucker diabetic fatty rats.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that plays an important role in glucose homeostasis. Its functions include glucose-stimulated insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and reduction in appetite and food intake. Despite the numerous antidiabetic properties of GLP-1, its therapeutic potential is limited by its short biological half-life due to rapid enzymatic degradation by dipeptidyl peptidase IV. The present study aimed to demonstrate the therapeutic effects of constitutively expressed GLP-1 in an overt type 2 diabetic animal model using an adenoviral vector system.
  
  
  METHODS
  A novel plasmid (pAAV-ILGLP-1) and recombinant adenoviral vector (Ad-ILGLP-1) were constructed with the cytomegalovirus promoter and insulin leader sequence followed by GLP-1(7-37) cDNA.
  
  
  RESULTS
  The results of an enzyme-linked immunosorbent assay showed significantly elevated levels of GLP-1(7-37) secreted by human embryonic kidney cells transfected with the construct containing the leader sequence. A single intravenous administration of Ad-ILGLP-1 into 12-week-old Zucker diabetic fatty (ZDF) rats, which have overt type 2 diabetes mellitus (T2DM), achieved near normoglycemia for 3 weeks and improved utilization of blood glucose in glucose tolerance tests. Circulating plasma levels of GLP-1 increased in GLP-1-treated ZDF rats, but diminished 21 days after treatment. When compared with controls, Ad-ILGLP-1-treated ZDF rats had a lower homeostasis model assessment for insulin resistance score indicating amelioration in insulin resistance. Immunohistochemical staining showed that cells expressing GLP-1 were found in the livers of GLP-1-treated ZDF rats.
  
  
  CONCLUSIONS
  These data suggest that GLP-1 gene therapy can improve glucose homeostasis in fully developed diabetic animal models and may be a promising treatment modality for T2DM in humans.
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Yongho
authors: Y
authors: Lee
authors: Mi Kyong
authors: MK
authors: Kwon
authors: Eun Seok
authors: ES
authors: Kang
authors: Young Mi
authors: YM
authors: Park
authors: Seung Ho
authors: SH
authors: Choi
authors: Chul Woo
authors: CW
authors: Ahn
authors: Kyung Sub
authors: KS
authors: Kim
authors: Chul Won
authors: CW
authors: Park
authors: Bong Soo
authors: BS
authors: Cha
authors: Sung Wan
authors: SW
authors: Kim
authors: Je Kyung
authors: JK
authors: Sung
authors: Eun Jig
authors: EJ
authors: Lee
authors: Hyun Chul
authors: HC
authors: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D052216:Glucagon-Like Peptide 1 / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D052216:Glucagon-Like Peptide 1