Grant: Project Grant

Incidences of obesity, type 2 diabetes (T2D) and fatty liver disease are increasing worldwide and these diseases are major contributors of morbidity and mortality. Excess intake of nutrient fuels, including carbohydrates, proteins and fats, can disturb the normal cellular functions in the body, resulting in accumulation of fat in adipose and liver leading to obesity, diabetes and fatty liver. Long-term exposure of the insulin producing pancreatic beta cells to high glucose and fat eventually causes their failure to produce insulin in response to changes in blood glucose levels. Even though glucose is needed by the body, when it is supplied in excess, it can lead to the production of toxic compounds in the cells that derail the normal cell function. We recently discovered an enzyme called glycerol 3-phosphate phosphatase (G3PP) and found that it acts as a glucose excess detoxification machine by converting it to a relatively innocuous substance, glycerol. We call this newly identified process "Glycerol shunt". Because human body uses glucose to make fat, decreasing the availability of glucose in cells helps in reducing the fat accumulation also. We now propose that the glycerol shunt orchestrated by G3PP is critical in preventing the deleterious effects of excess carbohydrate. We also plan to test if enhancing the function of G3PP, by increasing the expression of its gene, can prevent the development of diabetes, obesity and fatty liver disease in mouse models. We will also study the beneficial effects of G3PP in human cells. The findings from this research will help to better understand the importance of G3PP in protecting cells and tissues from the deleterious effects of excess carbohydrate and fat. The planned work should identify a new therapeutic avenue to address diseases like T2D, obesity and fatty liver, which affect millions of people worldwide.