Abstract
Circulating carbohydrates are an essential energy source, perturbations in which are pathognomonic of various diseases, diabetes being the most prevalent. Yet many of the genes underlying diabetes and its characteristic hyperglycaemia remain elusive. Here we use physiological and genetic interrogations in D. melanogaster to uncover the ‘glucome', the complete set of genes involved in glucose regulation in flies. Partial genomic screens of ∼1,000 genes yield ∼160 hyperglycaemia ‘flyabetes' candidates that we classify using fat body- and muscle-specific knockdown and biochemical assays. The results highlight the minor glucose fraction as a physiological indicator of metabolism in Drosophila. The hits uncovered in our screen may have conserved functions in mammalian glucose homeostasis, as heterozygous and homozygous mutants of Ck1alpha in the murine adipose lineage, develop diabetes. Our findings demonstrate that glucose has a role in fly biology and that genetic screenings carried out in flies may increase our understanding of mammalian pathophysiology.
Highlights
Circulating carbohydrates are an essential energy source, perturbations in which are pathognomonic of various diseases, diabetes being the most prevalent
Elucidating the ‘Glucome’, the complete set of genes involved in glucose regulation, may improve the understanding of the molecular underpinnings of glucose homeostasis, including those disrupted in diabetes, and thereby uncover new diagnostic and therapeutic strategies[9,10]
We found that fat body and muscle-restricted RNA interference (RNAi)-induced repression of insulin signalling components increased haemolymph glucose levels (Fig. 2e)
Summary
Environmental cues and metabolic mutations cause flyabetes. To test if haemolymph glucose is responsive to physiological cues in Drosophila, we examined glucose levels in several settings in which the mammalian blood glucose levels would vary and found that haemolymph glucose is subject to physiological and environmental regulation. We found that fat body and muscle-restricted RNAi-induced repression of insulin signalling components increased haemolymph glucose levels (Fig. 2e) These data support the potential that the UAS/Gal[4] system in conjunction with glucose measurements may be an effective screening tool for Glucome candidates, as observed in other studies, and one that could increase the understanding of tissue-specific and tissue-common roles. Ck1alpha emerged as a strong novel hyperglycaemia candidate in our RNAi-glucose screen; loss of Ck1alpha in both fat body and muscle of third instar larvae produced significant haemolymph glucose elevations 100% of the time. Age; both times we detected significantly elevated (fed) glucose in mutants (Fig. 8f,g); these mice seem to develop diabetes at a young age These data indicate that the deletion of one or two copies of CSNK1a1 in adipose tissues does not alter body or fat mass, but does produce significant hyperglycaemia. Ck1alpha/CSNK1a1 appears to regulate glucose metabolism in flies and mammals
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