More than 80% of people with type 2 diabetes mellitus (DM2), are obese. Yet, most obese people do not develop diabetes. A critical unsolved question is, what distinguishes obese individuals who are diabetes-resistant from those who are susceptible to diabetes? We have replicated the obesity/diabetes dichotomy in mice by studying an obese diabetes-resistant strain, C57BL/6 ob/ob (B6-ob) and an obese diabetes-susceptible congenic strain, BTBR.ob. We mapped three gene loci (termed t2dm1, t2dm2 &t2dm3) that control diabetes susceptibility in an F2 derived from these progenitors. The objective of this project is to positionally clone the genes underlying these quantitative trait loci (QTL) and identify their role in DM2 susceptibility. During the current grant period, we positionally cloned the locus underlying t2dm2, a locus associated with disrupted islet morphology and reduced insulin secretion in vivo. We narrowed the t2dm2 locus to a 242-kb interval comprising the promoter, one exon, and the first intron of the SorCS1 gene. We studied two different human populations to test the hypothesis that SorCS1 plays a role in diabetes susceptibility in humans. We found association of SorCS1 SNPs with plasma insulin, insulin secretion in a Mexican-American cohort in Los Angeles selected for the absence of diabetes but the presence of metabolic syndrome traits. We also found association of SorCS1 SNPs with age of onset of diabetes and diabetes risk in a Mexican-American cohort in San Antonio.
The aims of this proposal are to create a beta-cell-specific SorCS knockout mouse, to positionally clone the remaining two gene loci, t2dm1 and t2dm3. In addition, we shall test the hypothesis that the SorCS1 gene plays a role in islet angiogenesis. We shall identify genetic variants of the SorCS1 gene in our two Mexican-American cohorts and test these variants for binding to several ligands and for their ability to promote angiogenesis in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058037-10
Application #
7843596
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Abraham, Kristin M
Project Start
2000-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
10
Fiscal Year
2010
Total Cost
$544,820
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj et al. (2016) Genetic Architectures of Quantitative Variation in RNA Editing Pathways. Genetics 202:787-98
Shortreed, Michael R; Wenger, Craig D; Frey, Brian L et al. (2015) Global Identification of Protein Post-translational Modifications in a Single-Pass Database Search. J Proteome Res 14:4714-20
Bhatnagar, Sushant; Soni, Mufaddal S; Wrighton, Lindsay S et al. (2014) Phosphorylation and degradation of tomosyn-2 de-represses insulin secretion. J Biol Chem 289:25276-86
Ulbrich, Arne; Merrill, Anna E; Hebert, Alexander S et al. (2014) Neutron-encoded protein quantification by peptide carbamylation. J Am Soc Mass Spectrom 25:6-9
Munger, Steven C; Raghupathy, Narayanan; Choi, Kwangbom et al. (2014) RNA-Seq alignment to individualized genomes improves transcript abundance estimates in multiparent populations. Genetics 198:59-73
Kebede, Melkam A; Attie, Alan D (2014) Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends Endocrinol Metab 25:493-501
Johnson, Lisa M; Barrick, Stacey; Hager, Marlies V et al. (2014) A potent ?/?-peptide analogue of GLP-1 with prolonged action in vivo. J Am Chem Soc 136:12848-51
Neto, Elias Chaibub; Broman, Aimee T; Keller, Mark P et al. (2013) Modeling causality for pairs of phenotypes in system genetics. Genetics 193:1003-13
Lane, Rachel F; Steele, John W; Cai, Dongming et al. (2013) Protein sorting motifs in the cytoplasmic tail of SorCS1 control generation of Alzheimer's amyloid-? peptide. J Neurosci 33:7099-107

Showing the most recent 10 out of 50 publications