Abstract
Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.
Highlights
Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease
Targeted inactivation in Drosophila insulin-producing cells (IPCs) of Ilp2HF (Fig. 1b), insulin receptor[10], or glucose transporter[10] (Glut1) severely reduced production or secretion of Ilp[2], phenotypes observed after loss of insulin, insulin receptor or glucose transporter in mammalian islet beta cells
We describe an integrated, multisystem approach incorporating Drosophila genetics and physiology, and human islet biology to identify in vivo tissue-specific functions of candidate T2D risk genes
Summary
Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. The vast majority of T2D risk loci are associated with genes whose functions in glucose control and insulin output or responsiveness remain unknown To cut through this Gordian knot in diabetes genetics, it would be useful to (1) use conditional genetics, (2) assess the effects of gene perturbation on relevant in vivo physiological phenotypes, like insulin output, and (3) discover ways to test findings in appropriate primary human cells, like islet beta cells in culture or in vivo. We used novel methods for genetic perturbation in primary human islets to test the function of T2Drisk genes in primary human islet cells This identified a subset of genes like BCL11A that regulate human beta cell insulin secretion. Our work provides an experimental paradigm for unraveling the complex knot of genetics underlying the pathogenesis of T2D
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