title: Glucose-responsive artificial promoter-mediated insulin gene transfer improves glucose control in diabetic mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Based on these results, we suggest that insulin gene therapy might be one therapeutic option for remission of type 2 diabetes.
authors.affiliation: Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive N.W. Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Han
authors.forename: Eung-Hwi
authors.initials: EH
authors.lastname: Kim
authors.forename: Woohyuk
authors.initials: W
authors.lastname: Choi
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D051381:Rats; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin