A Genetic Strategy to Measure Circulating <i>Drosophila</i> Insulin Reveals Genes Regulating Insulin Production and Secretion

<div><p>Insulin is a major regulator of metabolism in metazoans, including the fruit fly <i>Drosophila melanogaster</i>. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (<i>Ilp2</i>) levels in <i>Drosophila</i>, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the <i>Drosophila</i> orthologues of human T2DM risk genes, including <i>GLIS3</i> and <i>BCL11A</i>, revealed roles of these <i>Drosophila</i> genes in Ilp2 production or secretion. Discovery of <i>Drosophila</i> mechanisms and regulators controlling <i>in vivo</i> insulin dynamics should accelerate functional dissection of diabetes genetics.</p>