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.
View: Text | PDF
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

×

Figure 5

UCn2 gene transfer increases glucose disposal in db/db mice.

Options: View larger image (or click on image) Download as PowerPoint
UCn2 gene transfer increases glucose disposal in db/db mice. Mice (db/db...
Mice (db/db) received i.v. AAV8.UCn2 (5 × 1011 gc) or saline and were studied 4 weeks after gene transfer. (A) UCn2 expression. UCn2 gene transfer was associated with a > 450-fold increase in liver mRNA expression 4 weeks after gene transfer (P = 0.0016). (B) Fasting glucose. Blood was sampled after a 12-hr fast in 5 male and 6 female db/db mice. One day after gene transfer (Day 1), mice that had received saline (db/db; n = 11) and UCn2 gene transfer (+UC, n = 11) had similar levels of hyperglycemia. However, 4 weeks later (Week 4), mice that had received UCn2 gene transfer had a 42% reduction in blood glucose (P = 0.0001). (C) Glucose tolerance test in db/db mice. Mice (db/db) received i.v. AAV8.UCn2 (+UCn2; 5 × 1011 gc, n = 5) or saline (db/db, n = 5). One month later, fasted mice (12 hr) received glucose (2 mg/g, i.p.), and glucose levels were measured (C). The AUC was reduced by 57% (P = 0.003). These results indicate that UCn2 gene transfer promotes glucose disposal and protects against hyperglycemia, confirming its efficacy in a second model of insulin resistance.