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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

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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 1

Vector map and studies in normal mice on standard diets.

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Vector map and studies in normal mice on standard diets.
(A) AAV8.UCn2 m...
(A) AAV8.UCn2 map. Initial studies in mice determined that AAV8.CBA.UCn2 is the optimal AAV serotype and promoter for the proposed studies resulting in a sustained increase in plasma UCn2 levels over 7 months (5). (B) Fasting glucose. Normal mice received i.v. AAV8.UCn2 (5 × 1011 gc, n = 8), saline (CON, n = 8), or AAV9.EGFP (5 × 1011 gc, n = 4) and standard chow for 3 weeks. A 24% reduction in fasting glucose was seen after AAV8.UCn2 gene transfer (P = 0.01). (C) AAV8.UCn2 dose-glucose response relationship. AAV8.UCn2 doses of 5 × 109 to 5 × 1011 gc produced 21%–33% reduction in fasting glucose levels in normal mice. We selected the highest dose (5 × 1011 gc) for studies conducted in insulin resistant mice. In all graphs, data are mean ±SEM; P values are from Student’s t test for unpaired data, 2 tails, unless stated otherwise.

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