A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion.
A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion.
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DOI：
10.1371/journal.pgen.1004555
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发表时间：
2014-08
期刊：
影响因子：
4.5
通讯作者：
Kim SK
中科院分区：
文献类型：
--
作者：
Park S;Alfa RW;Topper SM;Kim GE;Kockel L;Kim SK
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 in Drosophila, 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 Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics. 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 of Drosophila orthologues of diabetes risk genes revealed tissue-specific roles for these genes in regulating insulin production and secretion. These findings should accelerate use of Drosophila and other genetically-tractable systems to discover conserved mechanisms and regulators controlling in vivo insulin dynamics relevant to diabetes and other human diseases.
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