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

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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
Article numbere1002323
JournalPLoS Genetics
Volume7
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

diabetes
insulin secretion
Quantitative Trait Loci
noninsulin-dependent diabetes mellitus
secretion
Type 2 Diabetes Mellitus
Organism Cloning
molecular cloning
quantitative trait loci
Chromosomes, Human, Pair 16
Insulin
chromosome
mice
introgression
Qa-SNARE Proteins
chromosomes
glucose
polymorphism
Single Nucleotide Polymorphism
fasting

ASJC Scopus subject areas

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

Cite this

Bhatnagar, S., Oler, A. T., Rabaglia, M. E., Stapleton, D. S., Schueler, K. L., Truchan, N. A., ... 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

Positional cloning of a type 2 diabetes quantitative trait locus; Tomosyn-2, a negative regulator of insulin secretion. / Bhatnagar, Sushant; Oler, Angie T.; Rabaglia, Mary E.; Stapleton, Donald S.; Schueler, Kathryn L.; Truchan, Nathan A.; Worzella, Sara L.; Stoehr, Jonathan P.; Clee, Susanne M.; Yandell, Brian S.; Keller, Mark P.; Thurmond, Debbie C.; Attie, Alan D.

In: PLoS Genetics, Vol. 7, No. 10, e1002323, 10.2011.

Research output: Contribution to journalArticle

Bhatnagar, S, Oler, AT, Rabaglia, ME, Stapleton, DS, Schueler, KL, Truchan, NA, Worzella, SL, Stoehr, JP, Clee, SM, Yandell, BS, Keller, MP, Thurmond, DC & Attie, AD 2011, 'Positional cloning of a type 2 diabetes quantitative trait locus; Tomosyn-2, a negative regulator of insulin secretion', PLoS Genetics, vol. 7, no. 10, e1002323. https://doi.org/10.1371/journal.pgen.1002323
Bhatnagar, Sushant ; Oler, Angie T. ; Rabaglia, Mary E. ; Stapleton, Donald S. ; Schueler, Kathryn L. ; Truchan, Nathan A. ; Worzella, Sara L. ; Stoehr, Jonathan P. ; Clee, Susanne M. ; Yandell, Brian S. ; Keller, Mark P. ; Thurmond, Debbie C. ; Attie, Alan D. / Positional cloning of a type 2 diabetes quantitative trait locus; Tomosyn-2, a negative regulator of insulin secretion. In: PLoS Genetics. 2011 ; Vol. 7, No. 10.
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