Pancreatic Beta Cell Autophagy and Islet Transplantation

Insulin-secreting pancreatic beta cells are characterized by high rates of protein synthesis. The levels of insulin granules are kept constant by crinophagy and autophagy. Beta cell-specific deletion of Atg7, a critical member of the autophagic pathway, in mice leads to defective insulin secretion, accumulation of ubiquitinated protein aggregates, and beta cell apoptosis. Defective autophagy has been reported in the beta cells of animal models of diabetes and in human diabetic pancreas. Probable causes are increased demand for insulin, exposure to fatty acids, and deposition of aggregates of islet amyloid polypeptide. Fatty acids have been shown to interfere with autophagic flux under diabetic conditions. Interactions between the pathways of apoptosis and autophagy suggest that when there is excessive autophagy, the cellular defense mechanism may resort to the death pathway. Although islet transplantation is a promising therapy, loss of islets by apoptosis makes it less efficient. Islets isolated from donor pancreata are exposed to multiple stresses including ischemia/perfusion injury and hypoxia. Autophagy can play a protective role in the islet transplantation setting because it clears organelles damaged during islet isolation and can provide energy to beta cells during hypoxia-induced starvation. We have demonstrated that preconditioning islets with autophagy inducers results in significant protection when they are exposed to hypoxia. Correction of defects in the autophagic flux in isolated islets can be one of the approaches to improve islet transplantation outcome.