We are in the midst of an unprecedented obesity epidemic, which is causing an epidemic of type 2 diabetes (T2D). Obesity causes insulin resistance, resulting in an increased demand for insulin from pancreatic -cells. Genetic factors play a critical role in determining whether or not the -cells are capable of responding to the increased demand for insulin. In individuals where this insulin demand is not met, diabetes results and likely reflects some aspect of -cell impairment (development, proliferation, survival or insulin secretion). We positionally cloned Sorcs1, a gene that contributes to obesity-induced T2D. SORCS1 is associated with T2D and diabetes complications in humans. We derived Sorcs1 knockout (KO) mice and when obese, they develop diabetes. Pancreatic -cells from obese Sorcs1 KO mice have a severe deficiency in insulin granules, due to a dramatic increase in the post-translational degradation of insulin. We have shown that Sortilin, a protein related to Sorcs1, which is known to target proteins to the lysosome for degradation, binds to insulin. The pro-domain of Sorcs1 also binds to Sortilin and inhibits its activity. Our preliminary studies show that overexpression of Sortilin in -cells, in contrast to -cells overexpressing Sorcs1, decreases cellular insulin content. We hypothesize that Sorcs1 inhibits the ability of Sortilin to promote insulin degradation. The proposed studies will elucidate the role of Sorcs1 and Sortilin in determining the intracellular fate of insulin. We have identified two coding SNPs in human Sortilin (SORT1); one associated with reduced insulin levels and the other with elevated cholesterol. We will characterize these SNPs in SORT1 to understand their association with these distinct phenotypes. We will evaluate an allelic variant in mouse Sorcs1 that is associated with reduced insulin. Our proposed studies will elucidate a newly identified branch point that determines whether insulin is packaged in insulin granules, or is diverted towards degradation. We will characterize mutations in Sortilin and Sorcs1 that are associated with decreased insulin in humans and in mice. Insights from our work may provide clues to the development of novel therapeutic approaches aimed at preserving the insulin reserve of pancreatic -cells.
The genetic contribution to type 2 diabetes is mainly derived from genes affecting the function of pancreatic -cells. We have identified two genes that interact with each other and determine whether or not newly-synthesized insulin is degraded or packaged into insulin granules for secretion.
|Peng, Yajing; Shapiro, Samantha L; Banduseela, Varuna C et al. (2018) Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell 17:e12820|
|Mitok, Kelly A; Freiberger, Elyse C; Schueler, Kathryn L et al. (2018) Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion. J Biol Chem 293:5860-5877|
|Keller, Mark P; Gatti, Daniel M; Schueler, Kathryn L et al. (2018) Genetic Drivers of Pancreatic Islet Function. Genetics 209:335-356|
|Ye, Risheng; Gordillo, Ruth; Shao, Mengle et al. (2018) Intracellular lipid metabolism impairs ? cell compensation during diet-induced obesity. J Clin Invest 128:1178-1189|
|Zhang, Xingmin; Jiang, Shan; Mitok, Kelly A et al. (2017) BAIAP3, a C2 domain-containing Munc13 protein, controls the fate of dense-core vesicles in neuroendocrine cells. J Cell Biol 216:2151-2166|
|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|
|Yu, Qing; Canales, Alejandra; Glover, Matthew S et al. (2017) Targeted Mass Spectrometry Approach Enabled Discovery of O-Glycosylated Insulin and Related Signaling Peptides in Mouse and Human Pancreatic Islets. Anal Chem 89:9184-9191|
|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|
|Attie, Alan D (2015) How do reducing equivalents increase insulin secretion? J Clin Invest 125:3754-6|