Cholecystokinin attenuates ß-cell apoptosis in both mouse and human islets.

Loss of functional pancreatic ß-cell mass and increased ß-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic ß-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing ß-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes ß-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a ß-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human ß-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases ß-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote ß-cell survival in human islets and has therapeutic potential to preserve ß-cell mass in diabetes and as an adjunct therapy after transplant.

Cation-Independent Mannose 6-Phosphate Receptor Deficiency Enhances ß-Cell Susceptibility to Palmitate.

Palmitate attenuates insulin secretion and reduces the viability of insulin-producing cells. Previous studies identified the aberrant palmitoylation or mispalmitoylation of proteins as one mechanism by which palmitate causes ß-cell damage. In this report, we identify a role for lysosomal protein degradation as a mechanism by which ß cells defend themselves against excess palmitate. The cation-independent mannose 6-phosphate receptor (CI-MPR) is responsible for the trafficking of mannose 6-phosphate-tagged proteins to lysosomes via Golgi sorting and from extracellular locations through endocytosis. RINm5F cells, which are highly sensitive to palmitate, lack CI-MPR. The reconstitution of CI-MPR expression attenuates the induction of endoplasmic reticulum (ER) stress and the toxic effects of palmitate on RINm5F cell viability. INS832/13 cells express CI-MPR and are resistant to the palmitate-mediated loss of cell viability. The reduction of CI-MPR expression increases the sensitivity of INS832/13 cells to the toxic effects of palmitate treatment. The inhibition of lysosomal acid hydrolase activity by weak base treatment of islets under glucolipotoxic conditions causes islet degeneration that is prevented by the inhibition of protein palmitoylation. These findings indicate that defects in lysosomal function lead to the enhanced sensitivity of insulin-producing cells to palmitate and support a role for normal lysosomal function in the protection of ß cells from excess palmitate.