Glucose-responsive artificial promoter-mediated insulin gene transfer improves glucose control in diabetic mice.

AIM: To investigate the effect of insulin gene therapy using a glucose-responsive synthetic promoter in type 2 diabetic obese mice. METHODS: We employed a recently developed novel insulin gene therapy strategy using a synthetic promoter that regulates insulin gene expression in the liver in response to blood glucose level changes. We intravenously administered a recombinant adenovirus expressing furin-cleavable rat insulin under the control of the synthetic promoter (rAd-SP-rINSfur) into diabetic Lepr(db/db) mice. A recombinant adenovirus expressing ß-galactosidase under the cytomegalovirus promoter was used as a control (rAd-CMV-ßgal). Blood glucose levels and body weights were monitored for 50 d. Glucose and insulin tolerance tests were performed. Immunohistochemical staining was performed to investigate islet morphology and insulin content. RESULTS: Administration of rAd-SP-rINSfur lowered blood glucose levels and normoglycemia was maintained for 50 d, whereas the rAd-CMV-ßgal control virus-injected mice remained hyperglycemic. Glucose tolerance tests showed that rAd-SP-rINSfur-treated mice cleared exogenous glucose from the blood more efficiently than control virus-injected mice at 4 wk [area under the curve (AUC): 21  508.80 ± 2248.18 vs 62  640.00 ± 5014.28, P < 0.01] and at 6 wk (AUC: 29  956.60 ± 1757.33 vs 60  016.60 ± 3794.47, P < 0.01). In addition, insulin sensitivity was also significantly improved in mice treated with rAd-SP-rINSfur compared with rAd-CMV-ßgal-treated mice (AUC: 9150.17 ± 1007.78 vs 11  994.20 ± 474.40, P < 0.05). The islets from rAd-SP-rINSfur-injected mice appeared to be smaller and to contain a higher concentration of insulin than those from rAd-CMV-ßgal-injected mice. CONCLUSION: Based on these results, we suggest that insulin gene therapy might be one therapeutic option for remission of type 2 diabetes.