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

J Clin Invest. 2001 Jul;108(2):319-29. doi: 10.1172/JCI12029.

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 beta 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 beta 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 beta 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / genetics*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Pancreas / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Trans-Activators / biosynthesis
  • Trans-Activators / deficiency*
  • Trans-Activators / genetics

Substances

  • Homeodomain Proteins
  • RNA, Messenger
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein