Positional cloning of a type 2 diabetes quantitative trait locus; Tomosyn-2, a negative regulator of insulin secretion

Sushant Bhatnagar, Angie T. Oler, Mary E. Rabaglia, Donald S. Stapleton, Kathryn L. Schueler, Nathan A. Truchan, Sara L. Worzella, Jonathan P. Stoehr, Susanne M. Clee, Brian S. Yandell, Mark P. Keller, Debbie C. Thurmond, Alan D. Attie

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lep ob/ob and C57BL/6 (B6) Lep ob/ob mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congenic mice and narrowed the diabetes susceptibility locus to a 1.6 Mb region. Introgression of this 1.6 Mb fragment of the BTBR Chr 16 into lean B6 mice (B6.16 BT36-38) replicated the phenotypes of the consomic mice. Pancreatic islets from the B6.16 BT36-38 mice were defective in the second phase of the insulin secretion, suggesting that the 1.6 Mb region encodes a regulator of insulin secretion. Within this region, syntaxin-binding protein 5-like (Stxbp5l) or tomosyn-2 was the only gene with an expression difference and a non-synonymous coding single nucleotide polymorphism (SNP) between the B6 and BTBR alleles. Overexpression of the b-tomosyn-2 isoform in the pancreatic β-cell line, INS1 (832/13), resulted in an inhibition of insulin secretion in response to 3 mM 8-bromo cAMP at 7 mM glucose. In vitro binding experiments showed that tomosyn-2 binds recombinant syntaxin-1A and syntaxin-4, key proteins that are involved in insulin secretion via formation of the SNARE complex. The B6 form of tomosyn-2 is more susceptible to proteasomal degradation than the BTBR form, establishing a functional role for the coding SNP in tomosyn-2. We conclude that tomosyn-2 is the major gene responsible for the T2D Chr 16 quantitative trait locus (QTL) we mapped in our mouse cross. Our findings suggest that tomosyn-2 is a key negative regulator of insulin secretion.

Original languageEnglish (US)
Article numbere1002323
JournalPLoS Genetics
Volume7
Issue number10
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Fingerprint Dive into the research topics of 'Positional cloning of a type 2 diabetes quantitative trait locus; Tomosyn-2, a negative regulator of insulin secretion'. Together they form a unique fingerprint.

  • Cite this

    Bhatnagar, S., Oler, A. T., Rabaglia, M. E., Stapleton, D. S., Schueler, K. L., Truchan, N. A., Worzella, S. L., Stoehr, J. P., Clee, S. M., Yandell, B. S., Keller, M. P., Thurmond, D. C., & Attie, A. D. (2011). Positional cloning of a type 2 diabetes quantitative trait locus; Tomosyn-2, a negative regulator of insulin secretion. PLoS Genetics, 7(10), [e1002323]. https://doi.org/10.1371/journal.pgen.1002323