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Citations to this article

Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1
Melissa K. Thomas, … , Matthew S. Tenser, Joel F. Habener
Melissa K. Thomas, … , Matthew S. Tenser, Joel F. Habener
Published July 15, 2001
Citation Information: J Clin Invest. 2001;108(2):319-329. https://doi.org/10.1172/JCI12029.
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Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1

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Abstract

Monogenic forms of diabetes can result from mutations in genes encoding transcription factors. Mutations in the homeodomain transcription factor IDX-1, a critical regulator of pancreas development and insulin gene transcription, confer a strong predisposition to the development of diabetes mellitus in humans. To investigate the role of IDX-1 expression in the pathogenesis of diabetes, we developed a model for the inducible impairment of IDX-1 expression in pancreatic β cells in vivo by engineering an antisense ribozyme specific for mouse IDX-1 mRNA under control of the reverse tetracycline transactivator (rtTA). Doxycycline-induced impairment of IDX-1 expression reduced activation of the Insulin promoter but activated the Idx-1 promoter, suggesting that pancreatic β cells regulate IDX-1 transcription to maintain IDX-1 levels within a narrow range. In transgenic mice that express both rtTA and the antisense ribozyme construct, impaired IDX-1 expression elevated glycated hemoglobin levels, diminished glucose tolerance, and decreased insulin/glucose ratios. Metabolic phenotypes induced by IDX-1 deficiency were observed predominantly in male mice over 18 months of age, suggesting that cellular mechanisms to protect IDX-1 levels in pancreatic β cells decline with aging. We propose that even in the absence of Idx-1 gene mutations, pathophysiological processes that decrease IDX-1 levels are likely to impair glucose tolerance. Therapeutic strategies to attain normal glucose homeostasis by restoring normal IDX-1 levels may be of particular importance for older individuals with diabetes mellitus.

Authors

Melissa K. Thomas, Octavia N. Devon, Jee H. Lee, Andreas Peter, David A. Schlosser, Matthew S. Tenser, Joel F. Habener

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Total citations by year

Year: 2021 2013 2012 2011 2009 2008 2007 2006 2005 2004 2003 2002 Total
Citations: 1 1 2 3 2 1 2 1 1 2 4 2 22
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Citations to this article (22)

Title and authors Publication Year
Mutant Huntingtin Impairs Pancreatic β-cells by Recruiting IRS-2 and Disturbing the PI3K/AKT/FoxO1 Signaling Pathway in Huntington’s Disease
L Li, Y Sun, Y Zhang, W Wang, C Ye
Journal of Molecular Neuroscience 2021
Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency
ED Franco, C Shaw-Smith, SE Flanagan, EL Edghill, J Wolf, V Otte, F Ebinger, P Varthakavi, T Vasanthi, S Edvardsson, AT Hattersley, S Ellard
Diabetic Medicine 2013
Conditional gene expression systems in the transgenic rat brain
K Schönig, T Weber, A Frömmig, L Wendler, B Pesold, D Djandji, H Bujard, D Bartsch
BMC Biology 2012
Maintenance of  -Cell Maturity and Plasticity in the Adult Pancreas: Developmental Biology Concepts in Adult Physiology
M Szabat, FC Lynn, BG Hoffman, TJ Kieffer, DW Allan, JD Johnson
Diabetes 2012
β-Cell Specific Overexpression of GPR39 Protects against Streptozotocin-Induced Hyperglycemia
KL Egerod, C Jin, PS Petersen, N Wierup, F Sundler, B Holst, TW Schwartz
International Journal of Endocrinology 2011
Metabolic syndrome in mice induced by expressing a transcriptional activator in adipose tissue
L Zhang, Y Zhou, AY Zhu, X Li, SS Mundt, L Gao, JM Lisnock, M Hernandez, M Alonso-Galicia, MS Springer, EA O’Neill, BL Daugherty, O Puig
Transgenic Research 2011
Type 2 Diabetes and the Aging Pancreatic Beta Cell
U Gunasekaran, M Gannon
Aging 2011
A new mouse model for temporal- and tissue-specific control of extracellular superoxide dismutase
Y Zou, CH Chen, JR Fike, TT Huang
genesis 2009
Modeling multiple sclerosis in laboratory animals
B Schreiner, FL Heppner, B Becher
Seminars in Immunopathology 2009
PDX-1 interaction and regulation of the Pancreatic Derived Factor (PANDER, FAM3B) promoter
BR Burkhardt, JR Cook, RA Young, BA Wolf
Biochimica et Biophysica Acta 2008
A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis
DA Babu, TG Deering, RG Mirmira
Molecular Genetics and Metabolism 2007
Transcriptional regulation of the distal promoter of the rat pyruvate carboxylase gene by hepatocyte nuclear factor 3β/Foxa2 and upstream stimulatory factors in insulinoma cells
T Boonsaen, P Rojvirat, KH Surinya, JC Wallace, S Jitrapakdee
Biochemical Journal 2007
Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2
SY Yeom, GH Kim, CH Kim, HD Jung, SY Kim, JY Park, YK Pak, DK Rhee, SQ Kuang, J Xu, DJ Han, DK Song, JW Lee, KU Lee, SW Kim
Molecular and cellular biology 2006
Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells
H Wang, M Iezzi, S Theander, PA Antinozzi, BR Gauthier, PA Halban, CB Wollheim
Diabetologia 2005
Identification of PCIF1, a POZ Domain Protein That Inhibits PDX-1 (MODY4) Transcriptional Activity
A Liu, BM Desai, DA Stoffers
Molecular and cellular biology 2004
Transcriptional networks controlling pancreatic development and beta cell function
JM Servitja, J Ferrer
Diabetologia 2004
Increased islet apoptosis in PDX-1+/- mice
James D. Johnson, Noreen T. Ahmed, Dan S. Luciani, Zhiqiang Han, Hung Tran, Jun Fujita, Stanley Misler, Helena Edlund, Kenneth S. Polonsky
Journal of Clinical Investigation 2003
Lessons for human diabetes from experimental mouse models
RN Kulkarni, A Zisman
Current Diabetes Reports 2003
Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes
Z Wang, E Moro, K Kovacs, R Yu, S Melmed
Proceedings of the National Academy of Sciences 2003
Developmental aspects of the endocrine pancreas
Daniel M Kemp, Melissa K Thomas, Joel F Habener
Reviews in Endocrine and Metabolic Disorders 2003
PDX1 restores beta-cell function in IRS2 knockout mice
Jake A. Kushner, Jing Ye, Markus Schubert, Deborah J. Burks, Matthew A. Dow, Carrie L. Flint, Sanjoy Dutta, Christopher V.E. Wright, Marc R. Montminy, Morris F. White
Journal of Clinical Investigation 2002
Experimental control of pancreatic development and maintenance
AM Holland, MA Hale, H Kagami, RE Hammer, RJ MacDonald
Proceedings of the National Academy of Sciences 2002

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