Transcription factors specifically regulate the temporal and spatial expression of their defined target genes and are thereof responsible for specificity and maintenance of tissue diversity. Models with depletion of transcription factor, insulin promoter factor (IPF)-1 (also called PDX-1) (MODY4) are characterized by reduced insulin gene expression and impaired pancreatic development and remodeling during neogenesis. The transcription factor IPF-1/PDX-1 was
the first transcription factor identified that directly regulates the expression of the insulin gene and the somatostatin gene in the pancreatic P-cell. Further examinations indicate its pivotal role in the development, general gene expression and maintenance of the P-cell. Examples of IPF-1/ PDX-1 regulated genes are glucokinase or GLUT2 and the glucose-regulated expression of the insulin gene is regulated by IPF-1/PDX-1 (33,34). Mutations in IPF-1/PDX-1 are the molecular cause of MODY4 but the prevalence of MODY4 is still low (35,36).
Mouse models deficient in the transcription factor NeuroD1/Beta2 (MODY6) show reduced P-cell number, altered P-cell morphology and develop neonatal diabetes as well as die within the first week after delivery (35,37-43). Like IPF-1/PDX-1 NeuroD1/Beta2 is a direct regulator of the insulin gene (41) and furthermore involved in pancreatic development. Mutations in NeuroDl/ Beta2 have been identified in one Icelandic and one European family fulfilling the diagnostics criteria for MODY (13,36). Recently, in certain populations HNF-4a or NeuroD1/Beta2 mutations have been suspected to be also involved in late-onset type 2 diabetes (13,30).
Although a clear association of a mutation in one of the MODY genes with the respective clinical phenotype has been identified, it still remains unclear how these misfunctions of genes involved can result in a disturbed insulin secretion. Interestingly, approximately 20% of patients with clinical features of MODY do not carry a mutation in one of the known MODY genes indicating further subtypes of MODY X with different genetic mutations in genes unidentified up to know.
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