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

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 6

β-Zfp148-KO mice show enhanced glucose tolerance during oGTT.

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β-Zfp148-KO mice show enhanced glucose tolerance during oGTT. Plasma gl...
Plasma glucose (A) and insulin (C) responses during an oGTT performed on female and male control (Zfp148fl/fl) and β cell–specific Zfp148 knockout (β-Zfp148-KO) mice maintained on either chow diet (n = 8, 6 Zfp148fl/fl and β-Zfp148-KO female and male mice, respectively) or the HF/HS diet (n = 8 female each and n = 11, 7 for male Zfp148fl/fl and β-Zfp148-KO mice, respectively); AUC for glucose (B) and insulin (D). Ex vivo secretion measurements on Zfp148fl/fl and β-Zfp148-KO female and male mice maintained on either chow diet (n = 5, 3, 3 and 3, respectively), or the HF/HS diet (n = 5, 6, 5 and 5, respectively) (E). Insets show total islet insulin content (ng Ins/islet) for each sex/diet group. Total number of islets harvested per mouse maintained on either chow diet (n = 5, 3, 3, and 5, respectively) or the HF/HS diet (n = 6, 6, 8 and 8, respectively) for Zfp148fl/fl and β-Zfp148-KO female and male mice, respectively (F). Insulin secretion measurements during islet perifusion for HF/HS diet–fed female (n = 5, 4) and male (n = 5, 7) Zfp148fl/fl and β-Zfp148-KO mice, respectively (G). Islets were exposed to 16.7 mM glucose from 0 minutes to 30 minutes. Insets, total insulin content per islet for perifusion studies. AUC for insulin values in response to 16.7 mM glucose determined during perifusion studies (H). *P < 0.05; **P < 0.01 for Zfp148fl/fl versus β-Zfp148-KO mice, for Student’s 2-tailed t test.