Experimental models of transcription factor-associated maturity-onset diabetes of the young.

Abstract

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 II 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: Haiyan Wang, Kerstin Hagenfeldt-Johansson, Luc A Otten, Benoit R Gauthier, Pedro L Herrera, Claes B Wollheim
• Journal: Diabetes (Diabetes) Vol. 51 Suppl 3 Pg. S333-42 (Dec 2002) ISSN: 0012-1797 [Print] United States
• PMID: 12475772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• DNA-Binding Proteins
• HNF1A protein, human
• HNF1B protein, human
• Hepatocyte Nuclear Factor 1-alpha
• Nuclear Proteins
• Transcription Factors
• Hepatocyte Nuclear Factor 1
• Hepatocyte Nuclear Factor 1-beta

Topics

• Animals
• Animals, Genetically Modified
• DNA-Binding Proteins
• Diabetes Mellitus, Type 2 (physiopathology)
• Hepatocyte Nuclear Factor 1
• Hepatocyte Nuclear Factor 1-alpha
• Hepatocyte Nuclear Factor 1-beta
• Humans
• Mutation (physiology)
• Nuclear Proteins
• Transcription Factors (genetics, metabolism)