TY - JOUR
T1 - One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance
AU - Gao, Mei Hua
AU - Giamouridis, Dimosthenis
AU - Lai, N. Chin
AU - Walenta, Evelyn
AU - Paschoal, Vivian Almeida
AU - Kim, Young Chul
AU - Miyanohara, Atsushi
AU - Guo, Tracy
AU - Liao, Min
AU - Liu, Li
AU - Tan, Zhen
AU - Ciaraldi, Theodore P.
AU - Schenk, Simon
AU - Bhargava, Aditi
AU - Oh, Da Young
AU - Hammond, H. Kirk
N1 - Funding Information:
We thank Ruoying Tang for her technical expertise and the UCSD Animal Care Program Phenotyping Core for performing the metabolic cage experiments. We thank Tamsin Lisa Kelly for reviewing the manuscript and providing helpful criticisms. This work was supported by NIH grants (P01 HL66941, HL088426, and DK080787); an NHLBI Gene Therapy Resource Program grant (HHSN268201200041C); VA Merit grant (1101BX001515); and UCSD School of Medicine Light Microscopy Facility (grant NS047101) for imaging.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/9/22
Y1 - 2016/9/22
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.88322
DO - 10.1172/jci.insight.88322
M3 - Article
C2 - 27699250
AN - SCOPUS:85055609013
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - e88322
ER -