Improving Pancreatic Beta-Cell Differentiation and Maturation through Epigenetic Modulation

Project Description Narrative:

Diabetes is the 7th leading cause of death in the U.S. The number of adults with diabetes has more than doubled in the last 20 years, with more than 37 million U.S. residents affected by the disease. Nearly one in 10 Wisconsinites suffer from diabetes and one in three suffer from prediabetes. The statewide economic impact of diabetes is substantial, with healthcare costs approaching $5.5 billion annually.

As diabetes prevalence negatively correlates with socioeconomic status, diabetes disproportionately affects racial and ethnic minorities in Wisconsin. African Americans and Latinos/Hispanics are two-to-three times more likely to be diagnosed with diabetes than White adults. Thus, generating novel therapies to treat diabetes will provide the people of Wisconsin with significant financial and health benefits. Diabetes is characterized by loss of functional β-cells in the islets of the pancreas via cell death or loss of cell identity through ‘de-differentiation’. Therefore, the pancreas no longer produces sufficient insulin to maintain normal blood glucose levels. Chronically high blood glucose levels damage blood vessels and nerves, leading to devastating complications like neuropathy, cardiovascular disease, or stroke. Replacing β-cells lost by cell death or restoring β-cell functional maturity via ‘re-differentiation’ holds promise as novel diabetes treatments.

This project will test the hypothesis that bromodomain and extraterminal domain bromodomain inhibition enhances human β-cell differentiation and maturation. This and corollary studies conducted by this project’s research team have significant therapeutic applications as they will provide superior islets to study islet biology and use in replacement therapies. These therapeutic strategies present a treatment option with long-lasting efficacy, replacing the current cost and access burdens associated with lifelong glucose monitoring and insulin therapies.