We are in the midst of an unprecedented epidemic of type 2 diabetes (T2DM). The proportion of the population with T2DM has doubled in just one generation. Although the epidemic is primarily driven by obesity, only ~20% of obese individuals develop T2DM. Genetic factors play a major role in determining who among obese individuals will progress to develop T2DM. The heritability of T2DM has been estimated to be approximately 0.5. Genetic studies in humans have identified many loci that contribute to diabetes susceptibility. Nearly all of these loci are involved in -cell biology. However, these loci only account for a small part of the high heritability of T2DM. A guiding premise of this grant proposal is that an important source of the missing heritability of human diabetes genetics is the inabiliy to carry out in-depth mechanistic phenotyping of beta-cell function. Here, we propose to carry out deep phenotyping of pancreatic islets to identify genes and pathways that confer susceptibility to T2DM. The project involves a hybrid strategy, employing two complementary mouse genetic cohorts: 1) a population of outbred mice and 2) a panel of recombinant inbred (RI) strains, both derived from the same founder population. This population, The Collaborative Cross, was derived from eight founder strains that together capture a major part of the genetic variability available in inbred mouse strains. Our preliminary studies of the founder strains revealed a high degree of phenotypic diversity in traits related to diabetes susceptibility. These results predict that the traits we propose to study will have strong heritability. Our team consist of a laboratory with extensive experience in islet biology and diabetes genetics together with four statistical geneticists who have developed many of the widely used methods for QTL mapping and causal network construction. We will carry out studies of insulin secretion, beta-cell proliferation and oxidative metabolism. In addition, we will conduct transcriptomic, proteomic, and phosphoproteomic studies on isolated pancreatic islets. In addition to classical association mapping, we will use genetic association data to construct causal networks linking gene loci with intermediate traits and disease phenotypes. Based on our prior experience with successful positional cloning projects, we predict that the loci we identify will be highly relevan to diabetes susceptibility in humans.

Public Health Relevance

The genetic contribution to type 2 diabetes is mainly derived from genes affecting beta-cell function. The diabetes phenotypes are brought on by environmental stressors, primarily obesity. This project will do extensive investigation of beta-cell biology in wo new mouse resources that facilitate gene discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101573-03
Application #
8996570
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Abraham, Kristin M
Project Start
2014-04-01
Project End
2019-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Earth Sciences/Resources
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Mitok, Kelly A; Freiberger, Elyse C; Schueler, Kathryn L et al. (2018) Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion. J Biol Chem 293:5860-5877
Keller, Mark P; Gatti, Daniel M; Schueler, Kathryn L et al. (2018) Genetic Drivers of Pancreatic Islet Function. Genetics 209:335-356
Ye, Risheng; Gordillo, Ruth; Shao, Mengle et al. (2018) Intracellular lipid metabolism impairs ? cell compensation during diet-induced obesity. J Clin Invest 128:1178-1189
Kreznar, Julia H; Keller, Mark P; Traeger, Lindsay L et al. (2017) Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes. Cell Rep 18:1739-1750
Attie, Alan D; Churchill, Gary A; Nadeau, Joseph H (2017) How mice are indispensable for understanding obesity and diabetes genetics. Curr Opin Endocrinol Diabetes Obes 24:83-91
Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj et al. (2016) Genetic Architectures of Quantitative Variation in RNA Editing Pathways. Genetics 202:787-98
Keller, Mark P; Paul, Pradyut K; Rabaglia, Mary E et al. (2016) The Transcription Factor Nfatc2 Regulates ?-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets. PLoS Genet 12:e1006466
Baughman, Joshua M; Rose, Christopher M; Kolumam, Ganesh et al. (2016) NeuCode Proteomics Reveals Bap1 Regulation of Metabolism. Cell Rep 16:583-595
Krautkramer, Kimberly A; Kreznar, Julia H; Romano, Kymberleigh A et al. (2016) Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues. Mol Cell 64:982-992
Morgan, Andrew P; Fu, Chen-Ping; Kao, Chia-Yu et al. (2015) The Mouse Universal Genotyping Array: From Substrains to Subspecies. G3 (Bethesda) 6:263-79

Showing the most recent 10 out of 12 publications