摘要
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 β-galactosidase under the cytomegalovirus promoter was used as a control(rAd-CMV-βgal).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-βgal 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-βgal-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-βgal-injected mice.CONCLUSION:Based on these results,we suggest that insulin gene therapy might be one therapeutic option for remission of type 2 diabetes.
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 β-galactosidase under the cytomegalovirus promoter was used as a control（rAd-CMV-βgal）.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-βgal 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-βgal-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-βgal-injected mice.CONCLUSION：Based on these results,we suggest that insulin gene therapy might be one therapeutic option for remission of type 2 diabetes.
基金
Supported by A grant from Innovative Research Institute for Cell Therapy Project,South Korea,No.A062260
