Gene loci associated with insulin secretion in islets from nondiabetic mice

• Published in: The Journal of clinical investigation 2019-10, Vol.129 (10), p.4419-4432
• Main Authors: Keller, Mark P, Rabaglia, Mary E, Schueler, Kathryn L, Stapleton, Donnie S, Gatti, Daniel M, Vincent, Matthew, Mitok, Kelly A, Wang, Ziyue, Ishimura, Takanao, Simonett, Shane P, Emfinger, Christopher H, Das, Rahul, Beck, Tim, Kendziorski, Christina, Broman, Karl W, Yandell, Brian S, Churchill, Gary A, Attie, Alan D
• Format: Article
• Language: English
• Subjects: Amino acids; Animal models; Beta cells; Biomedical research; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Disease susceptibility; Genes; Genetic aspects; Genetic diversity; Genetic engineering; Genetic research; Genetic screening; Genetic testing; Genome-wide association studies; Genomes; Genomics; Glucose; Human genome; Insulin; Insulin resistance; Insulin secretion; Kinases; Obesity; Phenols (Class of compounds); Phenotypes; Phosphatases; Protein kinase; Protein kinases; Protein-serine/threonine kinase; Protein-tyrosine-phosphatase; Quantitative genetics; Quantitative trait loci; Secretion; Single-nucleotide polymorphism; Synteny; Transcription (Genetics); Transgenic mice; Type 2 diabetes; Tyrosine; Zinc finger proteins
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI129143

Genetic susceptibility to type 2 diabetes is primarily due to [beta] cell dysfunction. However, a genetic study to directly interrogate [beta] 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 Kruppel-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.