A Genetic Strategy to Measure Circulating Drosophila Insulin Reveals Genes Regulating Insulin Production and Secretion
Sangbin Park, Ronald W. Alfa, Sydni M. Topper, Grace E. S. Kim, Lutz Kockel, Seung K. Kim mail
Abstract
Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. 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 (Ilp2) levels inDrosophila, 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 theDrosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophilamechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.
Author Summary
Genome-wide association studies in patients with type 2 diabetes mellitus have identified more than 65 loci, encoding up to 500 candidate susceptibility genes. Thus, investigators are fundamentally challenged to (i) screen and identify relevant candidates in vivo, (ii) determine if loss- or gain-of-function underlies the association, (iii) link perturbed gene function to hallmark type 2 diabetes mellitus physiological phenotypes like insulin production or secretion, and (iv) identify relevant tissue(s) where the biological function of a specific regulator is required. Here we exploit Drosophila genetics to reveal the molecular functions of evolutionally conserved regulators that are associated with human type 2 diabetes mellitus. Targeted knockdown ofDrosophila orthologues of diabetes risk genes revealed tissue-specific roles for these genes in regulating insulin production and secretion. These findings should accelerate use of Drosophilaand other genetically-tractable systems to discover conserved mechanisms and regulators controlling in vivo insulin dynamics relevant to diabetes and other human diseases.
Citation:Park S, Alfa RW, Topper SM, Kim GES, Kockel L, et al. (2014) A Genetic Strategy to Measure Circulating Drosophila Insulin Reveals Genes Regulating Insulin Production and Secretion. PLoS Genet 10(8): e1004555. doi:10.1371/journal.pgen.1004555
Editor: Paul H. Taghert, Washington University Medical School, United States of America Received: April 16, 2014; Accepted: June 20, 2014; Published: August 13, 2014
Copyright: © 2014 Park et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.
Funding: Work was supported by the Snyder Foundation and Howard Hughes Medical Institute. RWA is a student in the Stanford Medical Scientist Training Program and was also supported by fellowships from Soros Foundation and Stanford Bio-X program. SKK is an Investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
