Journal
DIABETES
Volume 51, Issue -, Pages S333-S342Publisher
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.51.2007.S333
Keywords
-
Categories
Ask authors/readers for more resources
Six monogenic forms of maturity-onset diabetes of the young (MODY) have been identified to date. Except for MODY2 (glucokinase), all other MODY subtypes have been linked to transcription factors. We have established a MODY3 transgenic model through the beta-cell-targeted expression of, dominant-negative HNF-1alpha either constitutively (rat insulin 11 promoter) or conditionally (Tet-On system). The animals display either overt diabetes or glucose intolerance. Decreased insulin secretion and reduced pancreatic insulin content contribute to the hyperglycemic state. The conditional approach in INS-1 cells helped to define new molecular targets of hepatocyte nuclear factor (HNF)-1alpha. In the cellular system, nutrient-induced insulin secretion was abolished because of impaired glucose metabolism. Conditional suppression of HNF-4alpha, the MODY1 gene, showed a similar phenotype in INS-1 cells to HNF-1alpha. The existence of a regulatory circuit between HNF-4alpha and HNF-1alpha is confirmed in these cell models. The MODY4 gene, IPF-1 (insulin promoter factor-1)/PDX-1 (pancreas duodenum homeobox-1), controls not only the transcription of insulin but also expression of enzymes involved in its processing. Suppression of Pdx-1 function in INS-1 cells does not alter glucose metabolism but rather inhibits insulin release by impairing. steps distal to the generation of mitochondrial coupling factors. The presented experimental models are important tools for the elucidation of the beta-cell pathogenesis in MODY syndromes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available