Type 2 diabetes (T2D) is a polygenic disorder with multiple risk alleles that interacts to reduce islet function and/or effective insulin secretion. Genetic factors are estimated to contribute approximately 50% towards the risk of T2D. The most important non-genetic factor in T2D is obesity; >80% of people with T2D are obese. Yet, most people who are obese are not diabetic. We have reproduced this obesity-T2D dichotomy in mice by studying two mouse strains, C57BL/6 and BTBR T (+) tf, which differ in obesity-induced T2D. Our hypothesis was that an insulin secretion defect should be manifest by increased fasting plasma glucose levels. By quantitative trait locus (QTL) mapping in an obese F2 mice, we identified a fasting plasma glucose locus on chromosome-16. Using interval-specific congenic strains to narrow the QTL, we discovered a single nucleotide polymorphism (SNP) (Ser912àLeu) in the protein coding region of the gene for tomosyn-2. Tomosyn-2 is a relatively uncharacterized protein that has a syntaxin binding domain; syntaxin being a member of the SNARE core complex that regulates exocytosis of insulin granules from the b-cell. We demonstrated a reduced capacity for insulin secretion in b-cells from mice congenic for the tomosyn-2 SNP, directly correlating with the hypoinsulinemic/hyperglycemic phenotype of the animals. Using biochemical techniques, we demonstrated that tomosyn-2 undergoes phosphorylation-dependent degradation and the coding SNP negatively impacted its protein turnover. Our recent studies are focused on identifying the role of tomosyn-2 as a negative regulator of insulin secretion and the mechanism by which b-cells reverses the inhibitory function of tomosyn-2 during glucose-dependent insulin secretion. Understanding the role of tomosyn-2 will provide new insights into the regulation of insulin secretion and emphasizes that negative regulation is critical for avoiding insulin-induced hypoglycemia.