One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance
Mei Hua Gao, Dimosthenis Giamouridis, N. Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P. Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, H. Kirk Hammond
Mei Hua Gao, Dimosthenis Giamouridis, N. Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P. Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, H. Kirk Hammond
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Research Article Therapeutics

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

Mei Hua Gao, Dimosthenis Giamouridis, N. Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P. Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, H. Kirk Hammond

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Figure 7

Weight gain and fatty infiltration of liver.

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Weight gain and fatty infiltration of liver. (A) Weight gain on HFD. Wei...
(A) Weight gain on HFD. Weights increased similarly in both groups for 8 weeks but were attenuated after UCn2 gene transfer (P = 0.002; repeated measures ANOVA). (B) Histology of liver and left ventricle. Mice fed HFDs for 5 weeks received i.v. UCn2 gene transfer (HFD + UCn2; 5 × 1011 gc) or saline (HFD), and HFD was maintained for 5 additional weeks. AAV8.UCn2 delivery and sustained urocortin 2 expression had no adverse effects on liver, LV, or skeletal muscle histology. Evident in the liver micrographs is fatty infiltration in HFD-fed but untreated mice. H&E and Masson’s trichrome staining were performed on sections of liver, transmural sections of left ventricle (LV), and skeletal muscle (Skl Mus). Trichrome + Con, positive control for Masson’s trichrome stain (scale bars: 100 μm). (C) Quantitative histological assessment of liver indicates that UCn2 gene transfer was associated with a 74% reduction in fatty infiltration of liver (P = 0.015; Student’s t test, unpaired, 2-tailed). Reduced fatty infiltration of the liver appeared to be independent of weight gain; it also was seen after UCn2 gene transfer in db/db mice despite no group difference in weight. (D) Liver triglyceride content. Livers from HFD-fed mice that received UCn2 gene transfer showed reduced triglyceride content (P = 0.024; Student’s t test, unpaired, 2-tailed).