Phenotypic Correction of Diabetic Mice by Adenovirus-Mediated Glucokinase Expression
- Urvi J. Desai1,
- Eric D. Slosberg2,
- Brian R. Boettcher2,
- Shari L. Caplan2,
- Barbara Fanelli2,
- Zouhair Stephan2,
- Vicky J. Gunther1,
- Michael Kaleko1 and
- Sheila Connelly1
- 1Genetic Therapy, Inc., Gaithersburg, Maryland
- 2Novartis Institute for Biomedical Research, Summit, New Jersey
Abstract
Hyperglycemia of diabetes is caused in part by perturbation of hepatic glucose metabolism. Hepatic glucokinase (GK) is an important regulator of glucose storage and disposal in the liver. GK levels are lowered in patients with maturity-onset diabetes of the young and in some diabetic animal models. Here, we explored the adenoviral vector–mediated overexpression of GK in a diet-induced murine model of type 2 diabetes as a treatment for diabetes. Diabetic mice were treated by intravenous administration with an E1/E2a/E3-deleted adenoviral vector encoding human hepatic GK (Av3hGK). Two weeks posttreatment, the Av3hGK-treated diabetic mice displayed normalized fasting blood glucose levels (95 ± 4.8 mg/dl; P < 0.001) when compared with Av3Null (135 ± 5.9 mg/dl), an analogous vector lacking a transgene, and vehicle-treated diabetic mice (134 ± 8 mg/dl). GK treatment also resulted in lowered insulin levels (632 ± 399 pg/ml; P < 0.01) compared with the control groups (Av3Null, 1,803 ± 291 pg/ml; vehicle, 1,861 ± 392 pg/ml), and the glucose tolerance of the Av3hGK-treated diabetic mice was normalized. No significant increase in plasma or hepatic triglycerides, or plasma free fatty acids was observed in the Av3hGK-treated mice. These data suggest that overexpression of GK may have a therapeutic potential for the treatment of type 2 diabetes.
Footnotes
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Address correspondence and reprint requests to Sheila Connelly, Genetic Therapy, Inc., 9 West Watkins Mill Rd., Gaithersburg, MD 20878. E-mail: sheila.connelly{at}pharma.novartis.com.
Received for publication 11 September 2000 and accepted in revised form 27 June 2001.
U.J.D., M.K., and S.C. are employed by Genetic Therapy, Inc., a Novartis company, which manufactures and markets pharmaceuticals related to the treatment of diabetes and its complications. V.J.G. was employed by Genetic Therapy, Inc., when she contributed to the research incorporated in this article but is now an employee of GenVec. E.D.S., B.R.B., S.L.C., and B.F. are employed by Novartis Pharmaceutical Corporation, which manufactures and markets pharmaceuticals related to the treatment of diabetes and its complications; E.D.S. and B.R.B. also hold stock in Novartis Pharmaceutical Corporation.
ALT, alanine transaminase; BSA, bovine serum albumin; FFA, free fatty acids; GK, glucokinase; H&E, hematoxylin and eosin; HBSS, Hank’s balanced salt solution; MODY, maturity-onset diabetes of the young; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction; TBS, Tris-buffered saline; TG, triglycerides.
