The beta cell is dedicated to the synthesis and secretion of insulin, and is exquisitely adapted to alterations in nutrient supply over the short, medium and longer terms. Failure of these adaptive mechanisms for regulating insulin secretion, and a separate susceptibility to death by apoptosis, underlies the beta failure of T2D.

It is increasingly recognized that beta cell lipid metabolism plays a key role in both the physiological regulation of insulin secretion, and in beta failure, especially under the conditions of lipid oversupply (lipotoxicity) that accompanies obesity. In recent years my lab has embarked on comprehensive investigation of beta cell lipid metabolism by employing mass spectroscopy. This lipidomic analysis has provided new insights into the roles of different lipid species, acting in different intracellular compartments in regulating both insulin secretion and beta cell apoptosis.

Previously we had demonstrated that endoplasmic reticulum (ER) stress contributes to lipotoxic beta cell death and human T2D. Furthermore, we showed that disrupted trafficking of secretory cargo from ER to golgi underlies ER stress. We have now linked these phenomena mechanistically with a depletion of sphingomyelin and cholesterol, specifically in the ER compartment of the beta cell.

We have also identified a role for the lysosome in regulating neutral lipid metabolism in beta cells by a specialized form of autophagy known as lipophagy. In this process mobilization of neutral lipid stores (lipid droplets) by lysosomal acid lipase acts as a constitutive negative regulator of glucose stimulated insulin secretion.

These studies highlight the importance of applying comprehensive lipidomics with microscopic imaging to delineate roles of different lipid species in different subcellular compartments of the beta cell.