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

Monogenic forms of diabetes can result from mutations in genes encoding tra nscription factors. Mutations in the homeodomain transcription factor IDX-1 , a critical regulator of pancreas development and insulin gene transcripti on, 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 exp ression in pancreatic beta cells in vivo by engineering an antisense ribozy me specific for mouse IDX-1 mRNA under control of the reverse tetracycline transactivator (rtTA), Doxycycline-induced impairment of IDX-1 expression r educed activation of the Insulin promoter but activated the Idx-1 promoter, suggesting that pancreatic beta cells regulate IDX-1 transcription to main tain IDX-1 levels within a narrow range. In transgenic mice that express bo th rtTA and the antisense ribozyme construct, impaired IDX-1 expression ele vated glycated hemoglobin levels, diminished glucose tolerance, and decreas ed 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 beta cells decline with aging. We propose that even in the absence of Idx-1 gene mutat ions, 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 importanc e for older individuals with diabetes mellitus.