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Restoration of insulin receptor improves diabetic phenotype in T2DM mice
Yichen Wang, … , Oksana Palyha, James Mu
Yichen Wang, … , Oksana Palyha, James Mu
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e124945. https://doi.org/10.1172/jci.insight.124945.
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Research Article Metabolism Therapeutics

Restoration of insulin receptor improves diabetic phenotype in T2DM mice

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Abstract

Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.

Authors

Yichen Wang, Heather Zhou, Oksana Palyha, James Mu

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Figure 4

Injection of AAV-hIR rescued diabetic phenotype in mice.

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Injection of AAV-hIR rescued diabetic phenotype in mice.
(A) Blood gluco...
(A) Blood glucose levels were monitored from 0 to 5 weeks after AAV-hIR or control AAV injection (n = 7–12). Four weeks after virus injection, WT and ob/ob mice were fasted for 5 hours and then subjected to measurements of (B) fasting blood glucose levels (n = 12) and (C) plasma insulin levels (n = 5–8). Five weeks after virus injection, (D) ob/ob and (E) WT mice were subjected to insulin tolerance test (n = 10). Glucose AUCs (F and G) were calculated according to data in D and E, respectively. (H) Liver TGs (n = 7–10), (I) plasma TGs (n = 7–10), and (J) plasma FFAs (n = 3–4) were measured using terminal liver or blood samples. Data shown as mean ± SEM. Statistical analysis for 2-group comparison was conducted by t test (*P < 0.05, **P < 0.01). Otherwise in the case of multiple groups, comparisons were conducted by 1-way ANOVA test followed by Tukey’s multiple-comparisons test. Columns and data points marked with different letters in individual panels are significantly different from each other (P < 0.05).

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