Insulin is a peptide hormone made in islet beta-cells that is packaged into small storage vesicles, termed dense core granules. A beta-cell contains ~8000-10,000 insulin granules.
Insulin is initially synthesized as the prohormone precursor, proinsulin, in the endoplasmic reticulum. Proinsulin is subsequently trafficked to the Golgi, where it is sorted along with other regulatory cargo for packaging into regulated secretory vesicles. These regulatory vesicles emerge from the terminal Golgi, or trans-Golgi network, where they enter the storage pool to be used for glucose-stimulated insulin secretion. We can visualize the trafficking process using fluorescent reporters in live cells.
The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. We are currently exploring metabolic pathways that may contribute TCA-derived cytosolic coupling factors to the regulation of glucose-stimulated insulin secretion.
Early in response to insulin resistance and hyperglycemia, islet beta-cells increase insulin production, in part, through remodeling the secretory system; however the cellular mechanisms regulating this process are not well understood.
Long-term this strategy fails, which we hypothesize are due to defects in proinsulin trafficking and insulin granule formation. Images above demonstrate the loss of insulin granules in Type 2 diabetic beta-cells.
To study this process, we use genetically-encoded biosensors to examine how insulin is synthesized, packaged, and stored.
We take a multi-disciplinary approach using genetic mouse models, ex vivo islet cell cultures including rodent and human tissue, islet transplantation, live cell fluorescent imaging, and proteomics.