Michele Solimena - Cell Biology of Pancreatic Beta Cells

Previous and current research

Our laboratory is interested in the cell biology of pancreatic β-cells, which produce and secrete insulin. A deficient output of insulin secretion relative to metabolic demands is the ultimate cause of all forms of diabetes mellitus. β-cells store the insulin hormone within organelles termed secretory granules, which undergo fusion with the plasma membrane and release insulin in response to high levels of circulating glucose. Prolonged glucose stimulation depletes β-cells of insulin secretory granules, which must be quickly replenished.

The main question we are addressing is how beta cells regulate the turnover of insulin secretory granules, including their biogenesis, exocytosis and destruction. A mechanistic description of these processes may provide insight into the pathogenesis of type 1 and type 2 diabetes and contribute to the development of novel approaches for its treatment. These studies may also have general implications in the field of neuropeptide and peptide-hormone secretion from neurons and other endocrine cells.

Specifically, we are addressing the following key questions:

1) How is a β-cell counting its own insulin secretory granules?
2) Which are the molecular signatures associated with granule aging?
3) What accounts for the reduced mobility and propensity to undergo exocytosis of older versus younger insulin secretory granules?
4) Which posttranscriptional mechanisms allow glucose and other stimuli to prompt the rapid biogenesis of insulin secretory granules?
5) Which retrograde signaling pathways couple the exocytosis of insulin secretory granules with regulation of beta cell gene expression and replication?

Moreover, we are pursuing:

1) The isolation and characterization of islet precursor cells as a potential source to generate new pancreatic islets for the therapy of diabetes
2) siRNA and small compound high-throughput screenings for the identification of genes and drugs of potential interest for the therapy of diabetes

A) Electron microscopy of insulin granules in a rat pancreatic islets
B) Differential imaging of younger (in green) vs older (in red) insluin granules in insulinoma cells
C) Nucleocytoplasmic translocation of the mRNA binding protein PTBP1 (in yellow) in beta cells upon stimulation with IBMX. Nuclei of islet cells are labeled in blue.

Future projects and goals

Selected publications