We are in the midst of an obesity epidemic, which is also leading to an epidemic of type 2 diabetes (T2D). Approximately half the heritability of diabetes susceptibility is due to genetic variation. Recent human genetic studies suggest that human diabetes is polygenic and that genes that contribute to diabetes susceptibility primarily affect ?-cell function rather than insulin action. The relationship between obesity and T2D exhibits the following dichotomy, which is at the heart of the diabetes field: >80% of people with T2D are obese and insulin resistant. However, most obese people do not develop T2D. This obesity/diabetes dichotomy was replicated in mice by studying two mouse strains (C57BL/6 &BTBR) that differ in diabetes induced by obesity. An F2 was created between the two strains and several quantitative trait loci (QTLs) controlling plasma glucose and insulin were mapped to high resolution, thereby identifying the genes underlying the QTLs. Tomosyn-2 is a major gene contributing to diabetes susceptibility of the BTBR mouse strain. The preliminary data show that Tomosyn-2 is an inhibitor of insulin secretion. The project has identified phosphorylation sites on Tomosyn-2 that are responsive to insulin secretagogues, and a SNP that affects the stability of the Tomosyn-2 protein. The overall hypothesis to be tested is that Tomosyn-2 imposes a break on insulin secretion that is relieved by secretagogue-induced signaling pathways. This hypothesis will be tested by pursuing four specific aims: 1) to identify the signaling pathways and phosphorylation sites involved in regulating Tomosyn-2;2) to elucidate the mechanistic consequences of Tomosyn-2 phosphorylation;3) to elucidate the mechanism by which Tomosyn-2 regulates insulin granule exocytosis;and 4) to discover the role of Tomosyn-2 interacting partners in the regulation of insulin secretion. An innovative feature of the work is that it studies an allelic variant with disrupted regulation. These studies will elucidate how beta cells prevent hypoglycemia by imposing a brake on insulin secretion and how this brake is lifted in response to insulin secretagogues. It will identify pathways that when disrupted can lead to increased susceptibility to obesity-induced type 2 diabetes.
The study of insulin secretion has focused on the mechanisms by which nutrients are sensed and recruit the exocytotic apparatus to release insulin into the bloodstream. Our discovery that subtle genetic variation of a protein that blocks insulin secretion can raise glucose levels establishes that negative regulation of insulin secretion is physiologically important, and that disruption of this regulation can contribute to tye 2 diabetes.
|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|
|Attie, Alan D; Churchill, Gary A; Nadeau, Joseph H (2017) How mice are indispensable for understanding obesity and diabetes genetics. Curr Opin Endocrinol Diabetes Obes 24:83-91|
|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|
Showing the most recent 10 out of 51 publications