Abstract
Type 2 diabetes (T2D) is one of the most common human diseases. QTL analysis of the diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats has identified numerous hyperglycemic loci. However, molecular characterization and/or gene identification largely remains to be elucidated due mostly to the weak genetic variances contributed by each locus. Here we utilized Drosophila melanogaster as a secondary model organism for functional evaluation of the candidate gene. We demonstrate that the tissue specific knockdown of a homologue of igf2bp2 RNA binding protein leads to increased sugar levels similar to that found in the OLETF rat. In the mutant, the expression of two of the insulin-like peptides encoded in the fly genome, dilp2 and dilp3, were found to be downregulated. Consistent with previous reports of dilp mutants, the imp mutant flies exhibited an extension of life span; in contrast, starvation tolerance was reduced. These results further reinforce the possibility that imp is involved in sugar metabolism by modulating insulin expression.
Highlights
The world health organization (WHO) currently estimates that over 300 million individuals worldwide suffer from diabetes, 90% being type 2 diabetes (T2D) [1]
T2D, the primary feature of which is a state of chronic elevation of plasma glucose levels, is a polygenic disease that is caused by a metabolic and hormonal imbalance between insulin secretion from pancreatic β-cells and insulin resistance in peripheral tissues
Much effort has been devoted to the development and characterization of monogenic diabetes animal models, which have led to significant advancements in our understanding of the genetic basis of glucose/lipid metabolisms as well as the molecular pathogenesis of complications [2]
Summary
The world health organization (WHO) currently estimates that over 300 million individuals worldwide suffer from diabetes, 90% being type 2 diabetes (T2D) [1]. In spite of the progress, the importance of polygenic or spontaneous diabetes models is not diminished because the majority of genetic variations that are causative for a complex disease are not amorphic, but hypomorphic [3,4,5]. There have been several studies reporting the successful positional cloning of QTLs by further extensive fine mapping of congenic strains [3]. In these cases the LOD scores of the QTL are relatively high (above 6.0) and consistently the identified mutations led to a more than twofold increase or reduction in expression levels [3, 4]. Rodent models should be used for functional probing of the candidate genes, yet the screening of a large
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