Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 8 December 2000:
Vol. 290. no. 5498, pp. 1959 - 1962
DOI: 10.1126/science.290.5498.1959
Prev | Table of Contents | Next

Reports

Glucose-Dependent Insulin Release from Genetically Engineered K Cells

Anthony T. Cheung,13 Bama Dayanandan,1 Jamie T. Lewis,1 Gregory S. Korbutt,2 Ray V. Rajotte,2 Michael Bryer-Ash,4 Michael O. Boylan,5 M. Michael Wolfe,5 Timothy J. Kieffer13*

Genetic engineering of non-beta cells to release insulin upon feeding could be a therapeutic modality for patients with diabetes. A tumor-derived K-cell line was induced to produce human insulin by providing the cells with the human insulin gene linked to the 5'-regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta  cells.

1 Departments of Medicine and Physiology, and
2 Department of Surgery, University of Alberta, Edmonton, AB T6G 2S2, Canada.
3 enGene, Inc., Edmonton, AB T6G 2T5, Canada.
4 Department of Medicine, University of Tennessee, Memphis, TN 38103, USA.
5 Section of Gastroenterology, Boston Medical Center, Boston, MA 02118, USA.
*   To whom correspondence should be addressed. E-mail: tim.kieffer{at}ualberta.ca

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo.
Y. Fujita, R. D. Wideman, M. Speck, A. Asadi, D. S. King, T. D. Webber, M. Haneda, and T. J. Kieffer (2009)
Am J Physiol Endocrinol Metab 296, E473-E479
   Abstract »    Full Text »    PDF »
Transient cytochalasin-D treatment induces apically administered rAAV2 across tight junctions for transduction of enterocytes.
Y.-Y. Fu, E. Sibley, and S.-C. Tang (2008)
J. Gen. Virol. 89, 3004-3008
   Abstract »    Full Text »    PDF »
Targeted Ablation of Glucose-dependent Insulinotropic Polypeptide-producing Cells in Transgenic Mice Reduces Obesity and Insulin Resistance Induced by a High Fat Diet.
M. C. Althage, E. L. Ford, S. Wang, P. Tso, K. S. Polonsky, and B. M. Wice (2008)
J. Biol. Chem. 283, 18365-18376
   Abstract »    Full Text »    PDF »
Glucokinase Thermolability and Hepatic Regulatory Protein Binding Are Essential Factors for Predicting the Blood Glucose Phenotype of Missense Mutations.
M. F. Pino, K.-A. Kim, K. D. Shelton, J. Lindner, S. Odili, C. Li, H. W. Collins, M. Shiota, F. M. Matschinsky, and M. A. Magnuson (2007)
J. Biol. Chem. 282, 13906-13916
   Abstract »    Full Text »    PDF »
Bitter stimuli induce Ca2+ signaling and CCK release in enteroendocrine STC-1 cells: role of L-type voltage-sensitive Ca2+ channels.
M. C. Chen, S. V. Wu, J. R. Reeve Jr., and E. Rozengurt (2006)
Am J Physiol Cell Physiol 291, C726-C739
   Abstract »    Full Text »    PDF »
Biological and biomaterial approaches for improved islet transplantation..
A. S. Narang and R. I. Mahato (2006)
Pharmacol. Rev. 58, 194-243
   Abstract »    Full Text »    PDF »
Reversal of Type 1 Diabetes by Engineering a Glucose Sensor in Skeletal Muscle.
A. Mas, J. Montane, X. M. Anguela, S. Munoz, A. M. Douar, E. Riu, P. Otaegui, and F. Bosch (2006)
Diabetes 55, 1546-1553
   Abstract »    Full Text »    PDF »
From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation.
J. V. Sagen, S. Odili, L. Bjorkhaug, D. Zelent, C. Buettger, J. Kwagh, C. Stanley, K. Dahl-Jorgensen, C. de Beaufort, G. I. Bell, et al. (2006)
Diabetes 55, 1713-1722
   Abstract »    Full Text »    PDF »
Prohormone Convertase 1/3 Is Essential for Processing of the Glucose-dependent Insulinotropic Polypeptide Precursor.
R. Ugleholdt, M.-L. H. Poulsen, P. J. Holst, J.-C. Irminger, C. Orskov, J. Pedersen, M. M. Rosenkilde, X. Zhu, D. F. Steiner, and J. J. Holst (2006)
J. Biol. Chem. 281, 11050-11057
   Abstract »    Full Text »    PDF »
Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP.
M. J. Theodorakis, O. Carlson, S. Michopoulos, M. E. Doyle, M. Juhaszova, K. Petraki, and J. M. Egan (2006)
Am J Physiol Endocrinol Metab 290, E550-E559
   Abstract »    Full Text »    PDF »
Release of Transgenic Human Insulin from Gastric G Cells: A Novel Approach for the Amelioration of Diabetes.
Y.-C. Lu, C. Sternini, E. Rozengurt, and E. Zhukova (2005)
Endocrinology 146, 2610-2619
   Abstract »    Full Text »    PDF »
Insights into the Structure and Regulation of Glucokinase from a Novel Mutation (V62M), Which Causes Maturity-onset Diabetes of the Young.
A. L. Gloyn, S. Odili, D. Zelent, C. Buettger, H. A. J. Castleden, A. M. Steele, A. Stride, C. Shiota, M. A. Magnuson, R. Lorini, et al. (2005)
J. Biol. Chem. 280, 14105-14113
   Abstract »    Full Text »    PDF »
Cell-Specific Expression of Glucose-Dependent-Insulinotropic Polypeptide Is Regulated by the Transcription Factor PDX-1.
L. I. Jepeal, Y. Fujitani, M. O. Boylan, C. N. Wilson, C. V. Wright, and M. M. Wolfe (2005)
Endocrinology 146, 383-391
   Abstract »    Full Text »    PDF »
Hepatocyte Growth Factor Preserves Beta Cell Mass and Mitigates Hyperglycemia in Streptozotocin-induced Diabetic Mice.
C. Dai, Y. Li, J. Yang, and Y. Liu (2003)
J. Biol. Chem. 278, 27080-27087
   Abstract »    Full Text »    PDF »
Studies with GIP/Ins cells indicate secretion by gut K cells is KATP channel independent.
S. Y. Wang, M. M.-Y. Chi, L. Li, K. H. Moley, and B. M. Wice (2003)
Am J Physiol Endocrinol Metab 284, E988-E1000
   Abstract »    Full Text »    PDF »
BETA2 Activates Transcription From the Upstream Glucokinase Gene Promoter in Islet {beta}-Cells and Gut Endocrine Cells.
J. M. Moates, S. Nanda, M. A. Cissell, M.-J. Tsai, and R. Stein (2003)
Diabetes 52, 403-408
   Abstract »    Full Text »    PDF »
Behavior in the Eukaryotic Secretory Pathway of Insulin-containing Fusion Proteins and Single-chain Insulins Bearing Various B-chain Mutations.
B.-y. Zhang, M. Liu, and P. Arvan (2003)
J. Biol. Chem. 278, 3687-3693
   Abstract »    Full Text »    PDF »
Kinetics of Liver Repopulation after Bone Marrow Transplantation.
X. Wang, E. Montini, M. Al-Dhalimy, E. Lagasse, M. Finegold, and M. Grompe (2002)
Am. J. Pathol. 161, 565-574
   Abstract »    Full Text »    PDF »
Combined Expression of Pancreatic Duodenal Homeobox 1 and Islet Factor 1 Induces Immature Enterocytes to Produce Insulin.
H. Kojima, T. Nakamura, Y. Fujita, A. Kishi, M. Fujimiya, S. Yamada, M. Kudo, Y. Nishio, H. Maegawa, M. Haneda, et al. (2002)
Diabetes 51, 1398-1408
   Abstract »    Full Text »    PDF »
Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells.
S. V. Wu, N. Rozengurt, M. Yang, S. H. Young, J. Sinnett-Smith, and E. Rozengurt (2002)
PNAS 99, 2392-2397
   Abstract »    Full Text »    PDF »
Transgenic Overexpression of Hepatocyte Growth Factor in the {beta}-Cell Markedly Improves Islet Function and Islet Transplant Outcomes in Mice.
A. Garcia-Ocana, R. C. Vasavada, A. Cebrian, V. Reddy, K. K. Takane, J.-C. Lopez-Talavera, and A. F. Stewart (2001)
Diabetes 50, 2752-2762
   Abstract »    Full Text »    PDF »
Gene and Cell-Replacement Therapy in the Treatment of Type 1 Diabetes: How High Must the Standards Be Set?.
P. A. Halban, S. E. Kahn, A. Lernmark, and C. J. Rhodes (2001)
Diabetes 50, 2181-2191
   Abstract »    Full Text »
Insulin Production by Human Embryonic Stem Cells.
S. Assady, G. Maor, M. Amit, J. Itskovitz-Eldor, K. L. Skorecki, and M. Tzukerman (2001)
Diabetes 50, 1691-1697
   Abstract »    Full Text »    PDF »
Glucose-induced Toxicity in Insulin-producing Pituitary Cells That Coexpress GLUT2 and Glucokinase. IMPLICATIONS FOR METABOLIC ENGINEERING.
R. N. Faradji, E. Havari, Q. Chen, J. Gray, K. Tornheim, B. E. Corkey, R. C. Mulligan, and M. A. Lipes (2001)
J. Biol. Chem. 276, 36695-36702
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)