MODY-fying gene expression in diabetes
Identification of genes that are regulated by the transcription factor HNF1alpha may explain its involvement in MODY3 diabetes.
HNF1α (hepatocyte nuclear factor 1) was originally isolated as a liver transcription factor. So it came as a sweet surprise to researchers when HNF1α was identified as the gene mutated in patients suffering from MODY3, maturity onset diabetes of the young subtype 3. As they report in the 15 August EMBO Journal Wang et al. (EMBO Journal 2000, 19:4257-4264) used a tetracyclin-regulated system to identify genes controlled by HNF1α. They expressed the most common diabetes-associated mutant form of HNF1α (P291fsinsC) in the INS-1 insulinoma cell line. This mutant form reduced the expression of several genes important for pancreatic β-cell function and inhibited expression of the insulin gene. Other genes suppressed by HNF1α include those involved in glucose transport (GLUT2) and glycolysis (e.g. encoding proteins aldolase B and L-pyruvate kinase). These inhibitory effects result in reduced cellular insulin, insulin secretion and ATP production.