title: One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance.
abstract: Using mice rendered insulin resistant with high fat diets (HFD), we examined blood glucose levels and insulin resistance after i.v. delivery of an adeno-associated virus type 8 encoding murine urocortin 2 (AAV8.UCn2). A single i.v. injection of AAV8.UCn2-normalized blood glucose and glucose disposal within weeks, an effect that lasted for months. Hyperinsulinemic-euglycemic clamps showed reduced plasma insulin, increased glucose disposal rates, and increased insulin sensitivity following UCn2 gene transfer. Mice with corticotropin-releasing hormone type 2-receptor deletion that were rendered insulin resistant by HFD showed no improvement in glucose disposal after UCn2 gene transfer, indicating that the effect requires UCn2's cognate receptor. We also demonstrated increased glucose disposal after UCn2 gene transfer in db/db mice, a second model of insulin resistance. UCn2 gene transfer reduced fatty infiltration of the liver in both models of insulin resistance. UCn2 increases Glut4 translocation to the plasma membrane in skeletal myotubes in a manner quantitatively similar to insulin, indicating a mechanism through which UCn2 operates to increase insulin sensitivity. UCn2 gene transfer, in a dose-dependent manner, is insulin sensitizing and effective for months after a single injection. These findings suggest a potential long-term therapy for clinical type-2 diabetes.
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Giamouridis
authors.affiliation: Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Walenta
authors.affiliation: Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Vivian Almeida
authors.initials: VA
authors.lastname: Paschoal
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Ob-Gyn and The Osher Center for Integrative Medicine, UCSF, San Francisco, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Ob-Gyn and The Osher Center for Integrative Medicine, UCSF, San Francisco, California, USA.|Department of Medicine, First Hospital of Qinhuangdao, Hebei Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tan
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.affiliation: Department of Orthopedic Surgery, UCSD, San Diego, California, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.affiliation: Department of Ob-Gyn and The Osher Center for Integrative Medicine, UCSF, San Francisco, California, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, UCSD, San Diego, California, USA.
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: D000818:Animals; D001786:Blood Glucose; D000229:Dependovirus; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics; D054832:Urocortins / Q000008:administration & dosage*
chemical_list: D001786:Blood Glucose; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins