Gene loci associated with insulin secretion in islets from non-diabetic mice.
Document Type
Article
Publication Date
10-2019
Keywords
JMG
JAX Source
J Clin Invest 2019 Oct; 129(10):4419-4432
Volume
130
First Page
4419
Last Page
4432
ISSN
1558-8238
PMID
31343992
DOI
https://doi.org/10.1172/JCI129143
Grant
GM070683
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 >1,000-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 QTL from mouse are associated with diabetes-related SNPs in human genome-wide association studies. We report on three genes, Ptpn18, Hunk and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These three genes encode a non-receptor 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 non-diabetic individuals.
Recommended Citation
Keller M,
Rabaglia M,
Schueler K,
Stapleton D,
Gatti D,
Vincent M,
Mitok K,
Wang Z,
Ishimura T,
Simonett S,
Emfinger C,
Das R,
Beck T,
Kendziorski C,
Broman K,
Yandell B,
Churchill G,
Attie A.
Gene loci associated with insulin secretion in islets from non-diabetic mice. J Clin Invest 2019 Oct; 129(10):4419-4432