Metabolic regulation of ER redox homeostasis maintains insulin granule formation in pancreatic β-cells

Our blood sugar is tightly regulated by the hormone insulin, which is produced by clusters of cells in the pancreas, called β-cells. Insulin is the only hormone produced by the body that is capable of reducing blood sugar, highlighting the critical need to understand how β-cells regulate insulin production. The inability to control blood sugar, which commonly results in high blood sugar or hyperglycemia, results in diabetes mellitus, which causes several whole-body pathologies, including vision decline, kidney disease, heart disease, and an increased risk of stroke. In Type 2 diabetes (T2D), hyperglycemia is caused, in part, by the inability of the β-cells to produce enough insulin. The goal of my thesis work is to understand why β-cells fail to produce enough insulin in T2D to regulate blood sugar. To that end, my lab has developed a unique method to visually track insulin production in live β-cells using highly sophisticated microscopes. Using this tool, I have identified precise steps in the insulin production process that are defective in T2D.

The insulin molecule normally undergoes a complex folding process to reach its three-dimensional structure. Once formed, the final insulin structure is held in place by chemical linkages. If these linkages are absent, insulin structure is no longer stable, and the resulting insulin molecule is non-functional and degraded within the β-cell. This pathway serves as an important quality control step to ensure production of fully functional insulin molecules. My research has identified that in T2D, formation of these critical linkages, fail to occur and result in a significant loss of insulin production. Under T2D, linkages cannot form due to a change in the β-cell environment, resulting in an increase in oxidation. The insulin structure cannot be formed as efficiently under highly oxidizing conditions, leaving T2D β-cells susceptible to decreased insulin production.

Under non-diabetic conditions, antioxidant species are produced by a portion of the cell called the mitochondria to control the cellular environment. It is known that the mitochondria are unhealthy in T2D β-cells, but it is not known how β-cell mitochondria regulate the β-cell environment. Using sensors that calculate the oxidative status of mitochondrially-generated molecules that support insulin folding, I identified a direct role for antioxidants regulating the β-cell environment. In T2D, dysfunctional mitochondria lack the ability to produce antioxidants necessary for the formation of insulin structure, leading to an inability to control blood sugar. However, in mouse models of T2D, we can provide antioxidants and restore β-cell environment and insulin production to non-diabetic levels, which may provide a new treatment strategy for patients with T2D.