Obesity and Type 2 Diabetes

Obesity is a significant risk factor for type 2 diabetes (T2D). During obesity, certain sphingolipids, most notably ceramides, accumulate within insulin-resistant tissues of animals and humans including the pancreatic β-cells. In the pancreatic β-cells, ceramides inhibit insulin action, and induce apoptosis, inflammation, and stress responses.

Orosomucoid (Orm) proteins were recently identified as negative regulators of sphingolipid biosynthesis. Mammals have three Orm-like proteins (Ormdl1-3).

In vitro studies suggest that mammalian Ormdl3 alters endoplasmic reticulum-mediated calcium homeostasis, facilitates the unfolded protein response, induces cellular stress responses and plays a possible role in inflammation. In human genome-wide association studies, the ORMDL3 gene is strongly associated with inflammatory diseases, including asthma, Crohn’s disease, and diabetes. However, the expression, regulation, function, and importance of Ormdl proteins in β-cell physiology and pathology remain largely unknown.

By using a diversity of protocols that include mouse genetics, tissue-level analyses, flow cytometry, in vitro organelle function analysis, quantitative measurement of sphingolipid flux, lipidomics, metabolomics, and RNA-seq analyses, we will probe the function and regulation of these novel genes in the pancreatic islets in physiological and pathological states.