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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Article

Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1

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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Induction of impairment of IDX-1 expression in older RIP-rtTA/Tet-ASRZ-I...
Induction of impairment of IDX-1 expression in older RIP-rtTA/Tet-ASRZ-IDX-1 double-transgenic mice results in abnormal glucose tolerance. (a) Chronic doxycycline administration to older RIP-rtTA/Tet-ASRZ-IDX-1 double-transgenic male mice increases glycated hemoglobin levels. Double transgenic (tg/tg) or nontransgenic (WT) control male mice were treated with chronic oral doxycycline administration from weaning (doxycycline +). Age-matched double-transgenic male mice that were not treated with doxycycline (doxycycline –) comprised a second control group. After the mice were 18 months of age or older, glycated hemoglobin levels were measured. Data shown are the mean ± SEM of measurements from five to seven animals per group (*P ≤ 0.05; **P ≤ 0.01). (b) RIP-rtTA/Tet-ASRZ-IDX-1 double-transgenic mice have inducible defects in glucose tolerance. Double-transgenic mice older than 18 months of age with (+ dox) or without (– dox) chronic oral doxycycline administration underwent intraperitoneal glucose tolerance testing. Data shown are the mean ± SEM of measurements from four to six animals per treatment group for each sex (*P < 0.05; **P < 0.01). (c) Inducible impairment of IDX-1 protein expression in older double-transgenic mice after chronic doxycycline treatment. Mouse pancreatic extracts were analyzed by Western blotting with anti-IDX-1 antiserum (upper panels) and anti–Stat-3 antiserum (lower panels) as a loading control. Data shown are from three separate Western blots. Extracts were derived from male double-transgenic mice older than 18 months of age (old tg/tg) with (+) or without (–) chronic oral doxycycline treatment and male double-transgenic (young tg/tg) or wild-type (WT) mice 3 months of age after a 3-week course of oral doxycycline (+) or sucrose vehicle (–) treatment.