One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance
Mei Hua Gao, … , Da Young Oh, H. Kirk Hammond
Mei Hua Gao, … , Da Young Oh, H. Kirk Hammond
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e88322. https://doi.org/10.1172/jci.insight.88322.
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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 2

UCn2 gene transfer, glucose disposal, and insulin effectiveness in HFD-fed mice.

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UCn2 gene transfer, glucose disposal, and insulin effectiveness in HFD-f...
(A) Glucose tolerance test 16 weeks after HFD, UCn2 gene transfer before (Pre) vs. at 8 Weeks (Post). Mice received glucose (2 mg/g, i.p.), and glucose was measured sequentially for 120 min. AUC was reduced in mice that had received UCn2 gene transfer, whether it was administered before (+UCn2-Pre; n = 8) or 8 weeks after initiation of HFD (+UCn2-Post; n = 8) (P = 0.003, AUC). The similarity of UCn2-Pre and UCn2-Post glucose levels indicates that UCn2 not only prevented HFD-induced hyperglycemia, but also reduced it once present, indicating a treatment effect. (B) Plasma insulin. UCn2 gene transfer was associated with reduced insulin levels whether given before (Pre) or 8 weeks after (Post) initiation of HFD (P < 0.007; ANOVA). (C) Insulin tolerance test. Nonfasted mice received insulin (0.75 U/kg, i.p.) and blood glucose was assessed. UCn2 gene transfer (given at initiation of HFD) was associated with increased insulin sensitivity (P = 0.0004).