Type 2 diabetes (T2D) is the major health problem in the US that imposes significant physical, financial, and emotional tolls. Thus, there is a strong and urgent need for an effective and widely applicable therapy. Excessive accumulation of lipids in beta cells is considered to contribute to the development of T2D. At the same time, lipids supports insulin secretion. We aim to understand how an intracellular organelle termed lipid droplets (LDs) in beta cells regulate a double-edged sword action of lipids. Our work to date has shown that lipid droplet protein perilipin 2 and 5 (PLIN2 and 5) each has a unique role in beta cells to support insulin secretion and protects beta cells from nutritional stress. PLIN5 interacts with adipose triglycerides lipase (ATGL) and supports insulin secretion. PLIN2 sequestrates lipids as an inert pool and protects beta cells from lipid overload. However, beta cells cannot continue to accumulate lipids indefinitely. Thus, a pathway of LD clearance is important to maintain beta cell health under nutritional stress. Lipophagy is self-digestion of LDs at lysosome and known to play a role in LD clearance in a wide range of cells. Importantly, dysregulation of lipophagy has been associated with obese adipocytes and fatty liver. However, little is known regarding a role of lipophagy in beta cells. Our preliminary data showed that lipophagy is constitutively active in beta cells without nutrient deprivation. Interestingly, chronic suppression of LIPA in INS1 cells, rat islets, and human non- diabetic islets impairs insulin secretion. Therefore, we hypothesize that lysosomal degradation of LDs is critical for LD homeostasis and insulin secretion in beta cells, and that the impairment in lipophagy accelerates beta cell demise in T2D. The following three aims will test our hypothesis. Specific Aim 1: Determine how LIPA regulates LD catabolism and lipid metabolism in beta cells under regular and glucolipotoxic conditions: Our preliminary data indicates that LIPA and ATGL each has a distinct role in mobilization of LDs in beta cells. We will clarify how LIPA and ATGL confer the spatial and temporal regulation of lipid metabolism at LDs using beta cells in which LIPA and ATGL are down-regulated. Specific Aim 2: Determine a role of LIPA in the maintenance of beta cell function and health: Our preliminary data indicates that prolonged suppression of lipophagy negatively affects insulin secretion. We will address how LIPA deficiency affect beta cell health and function at regular and glucolipotoxic conditions. Specific Aim 3: Determine whether lipophagy dysfunction contributes to beta cell failure in T2D. It has been proposed that lysosome becomes dysfunctional in beta cells during the development of T2D. This could create functional deficiency of LIPA that requires the acidity of lysosome. In addition, nutritional stress may increase demand for clearance of LDs by lipophagy during the development of T2D. Here, we will test the rel...