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

PLoS Genet. 2011 Oct;7(10):e1002323. doi: 10.1371/journal.pgen.1002323. Epub 2011 Oct 6.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Chromosome Mapping
  • Cloning, Molecular
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Glucose / analysis
  • HEK293 Cells
  • Humans
  • Hypoglycemia / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Leptin / genetics
  • Leptin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Polymorphism, Single Nucleotide
  • Qa-SNARE Proteins / genetics
  • Qa-SNARE Proteins / metabolism
  • Quantitative Trait Loci / genetics
  • R-SNARE Proteins / genetics*
  • R-SNARE Proteins / metabolism*
  • Rats
  • SNARE Proteins / metabolism
  • Syntaxin 1 / genetics
  • Syntaxin 1 / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Insulin
  • Leptin
  • Qa-SNARE Proteins
  • R-SNARE Proteins
  • SNARE Proteins
  • STXBP5L protein, mouse
  • Syntaxin 1
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Glucose