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 October 29, 2019; First 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

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 5

Hunk is necessary for Western diet–induced islet dysfunction.

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Hunk is necessary for Western diet–induced islet dysfunction. Plasma gl...
Plasma glucose (A, B) and insulin (D, E) for Hunk-WT and Hunk-KO male mice maintained on either chow diet (n = 15 and 17, respectively) or the HF/HS diet (n = 8 each); AUC values for glucose (C) and insulin (F). Ex vivo insulin secretion measures for Hunk-WT and Hunk-KO male mice maintained on chow diet (G) (n = 14, 15) or HF/HS diet (H) (n = 8 each). Insets in G and H show total insulin content per islet for Hunk-WT and Hunk-KO mice. Ratio (HF/HS vs. chow diet) of insulin secretory responses (I). Insulin secretion during dynamic perifusion assay for Hunk-WT and Hunk-KO male mice maintained on chow diet (J) (n = 4 each) or HF/HS diet (K) (n = 3 and 5, respectively). Glucose was increased from 3.3 mM to 16.7 mM from time 0 to 40 minutes, after which glucose was returned to 3.3 mM. Insets in J and K show AUC for insulin responses during perifusion. Number of islets harvested per mouse (L); n = 23, 21 (chow), and n = 12 each (HF/HS) for Hunk-WT and Hunk-KO male mice, respectively. *P < 0.05 for Hunk-WT versus Hunk-KO, for Student’s 2-tailed t test. In G, H, and I, G indicates glucose.