Loss of the Drosophila nuclear receptor dHNF4 recapitulates Maturity Onset Diabetes of the Young 1. William E. Barry, Carl S. Thummel. Department of Human Genetics, University of Utah, Salt Lake City, UT.

   Nuclear receptors are ligand-regulated transcription factors that play critical roles in metabolism. Mutations in one of these, HNF4, lead to an inherited form of diabetes called Maturity Onset Diabetes of the Young 1 (MODY1). MODY1 is characterized by impaired glucose-stimulated insulin secretion and hyperglycemia that develop during early adulthood. Several studies have attempted to model MODY1 in mice through tissue-specific disruption of HNF4, yet none of these reported diabetes or reduced glucose-stimulated insulin secretion. Thus, it remains unclear how HNF4 regulates glucose homeostasis. In contrast, loss-of-function mutants for the single Drosophila HNF4 ortholog, dHNF4, faithfully recapitulate the MODY1 disease phenotype. dHNF4 mutants are sensitive to dietary sugar, dying as early adults. These animals display glucose intolerance, hyperglycemia and accumulate sorbitol and fructose, all of which are hallmarks of diabetes. dHNF4 protein localizes to the insulin producing cells in the adult brain and dHNF4 mutants display the hallmark symptom of MODY1 - a defect in glucose-stimulated secretion of Drosophila insulin-like peptides (DILPs). RNA-seq analysis of dHNF4 mutants identified a Drosophila homolog of Glucokinase (GK), Hexokinase C (HexC), as one of the most down-regulated genes. In mammals, GK is required in pancreatic beta cells and the liver for proper insulin secretion and the uptake of circulating glucose. In addition, GK mutations in humans lead to MODY2, a disease related to MODY1. Current efforts are focused on genetic rescue experiments to test the hypothesis that HexC is a critical downstream target of dHNF4. Taken together, our findings establish a model to understand the molecular mechanisms by which HNF4 regulates glucose homeostasis, and how mutations in this receptor contribute to MODY1. Our data also suggest that MODY1 and MODY2 may be linked through HNF4 regulation of GK expression. Finally, we have shown that nutrient sensing for DILP secretion differs between larval and adult stages, where glucose is sufficient to trigger secretion in adults.