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.
View: Text | PDF
Research Article Cell biology Genetics Article has an altmetric score of 14

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

×

Figure 2

The genetic architecture of insulin and glucagon secretion.

Options: View larger image (or click on image) Download as PowerPoint
The genetic architecture of insulin and glucagon secretion. Inferred QTL...
Inferred QTL (LOD ≥ 6) for ex vivo islet phenotypes determined from DO mice maintained on HF/HS diet. (A) Total islet content for insulin and glucagon (n = 482 mice each). (B) Insulin secretion in response to 7 different conditions; low (3.3 mM), medium (8.3 mM) or high (16.7 mM) glucose (G), medium glucose plus amino acids (aa; Leu, Ala and Gln) or the incretin hormone GLP1 (100 nM), high glucose plus palmitic acid (PA; 0.5 mM), or low glucose plus KCl (40 mM) (n = 479 mice). (C) Glucagon secretion in response to low glucose plus KCl (n = 365 mice). Secretion traits were mapped without or with conditioning ( | ) on the islet content for insulin (ins/islet) or glucagon (gcg/islet), or the concentration of glucose used for the condition (e.g., 16.7 mM for PA-induced secretion). Red = high LOD, yellow = low LOD. (D) Profile illustrating the number of QTL (LOD > 5) occurring within a 4 Mb genomic window. QTL hotspots with 7 or more co-mapping traits were identified on chromosomes 1, 3, and 9 (see black arrowheads). Supplemental Table 1 lists all QTL, their LOD scores, genomic position, and allele effect values at the peak.