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Gene loci associated with insulin secretion in islets from nondiabetic mice
Mark P. Keller, … , Gary A. Churchill, Alan D. Attie
Mark P. Keller, … , Gary A. Churchill, Alan D. Attie
Published July 25, 2019
Citation Information: J Clin Invest. 2019;129(10):4419-4432. https://doi.org/10.1172/JCI129143.
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Research Article Cell biology Genetics

Gene loci associated with insulin secretion in islets from nondiabetic mice

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Abstract

Genetic susceptibility to type 2 diabetes is primarily due to β cell dysfunction. However, a genetic study to directly interrogate β cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of secretagogues. Insulin secretion from DO islets ranged greater than 1000-fold even though none of the mice were diabetic. The insulin secretory response to each secretagogue had a unique genetic architecture; some of the loci were specific for one condition, whereas others overlapped. Human loci that are syntenic to many of the insulin secretion quantitative trait loci (QTL) from mice are associated with diabetes-related SNPs in human genome-wide association studies. We report on 3 genes, Ptpn18, Hunk, and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These 3 genes encode a nonreceptor type protein tyrosine phosphatase, a serine/threonine protein kinase, and a Krϋppel-type zinc-finger transcription factor, respectively. Our results demonstrate that genetic variation in insulin secretion that can lead to type 2 diabetes is discoverable in nondiabetic individuals.

Authors

Mark P. Keller, Mary E. Rabaglia, Kathryn L. Schueler, Donnie S. Stapleton, Daniel M. Gatti, Matthew Vincent, Kelly A. Mitok, Ziyue Wang, Takanao Ishimura, Shane P. Simonett, Christopher H. Emfinger, Rahul Das, Tim Beck, Christina Kendziorski, Karl W. Broman, Brian S. Yandell, Gary A. Churchill, Alan D. Attie

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Figure 1

Ex vivo insulin secretion measurements from 479 DO mice maintained on a Western-style diet.

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Ex vivo insulin secretion measurements from 479 DO mice maintained on a ...
Distribution of female (n = 240) and male (n = 239) DO mice. Black ticks show sex for each mouse. Insulin secretion was determined from single isolated islets in response to 7 conditions: 3.3, 8.3, and 16.7 mM glucose (G); the amino acids (aa) leucine (0.5 mM), alanine (1.25 mM), and glutamine (2 mM) plus 8.3 mM G; KCl (40 mM) plus 3.3 mM G; GLP1 (100 nM) plus 8.3 mM G; and the fatty acid (PA) palmitate (0.5 mM) plus 16.7 mM G. Heatmap illustrates the amount of insulin secreted into the medium for each condition. Mice are ordered by the median value of their insulin secretory responses to the 7 conditions, highlighting mice that demonstrated low (left side) versus high (right side) secretory capacity. Insulin secretion values are the geometric mean of 6 individual measurements/condition/mouse for 479 DO mice, yielding a total of approximately 20,000 measures.
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