1. Gene loci associated with insulin secretion in islets from nondiabetic mice
- Author
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Daniel M. Gatti, Rahul Das, Brian S. Yandell, Kelly A. Mitok, Ziyue Wang, Mark P. Keller, Donnie S. Stapleton, Matthew Vincent, Karl W. Broman, Kathryn L. Schueler, Shane P Simonett, Takanao Ishimura, Alan D. Attie, Mary E. Rabaglia, Gary A. Churchill, Christopher H. Emfinger, Tim Beck, and Christina Kendziorski
- Subjects
0301 basic medicine ,Genetically modified mouse ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Mice, Inbred Strains ,Mice, Transgenic ,Type 2 diabetes ,Protein Serine-Threonine Kinases ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Insulin Secretion ,Genetic variation ,medicine ,Genetic predisposition ,Animals ,Humans ,Genetic Predisposition to Disease ,Insulin ,nutritional and metabolic diseases ,General Medicine ,Protein Tyrosine Phosphatases, Non-Receptor ,medicine.disease ,DNA-Binding Proteins ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Genetic Loci ,030220 oncology & carcinogenesis ,Commentary ,Secretagogue ,Research Article ,Genome-Wide Association Study ,Transcription Factors ,Genetic screen - 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.
- Published
- 2019