Download 2016 department of medicine research day

2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: Neuropeptide Y: a signature of functionally immature beta cells in
pancreas development and diabetes
Presenter: Sangeeta Dhawan
Division: Endocrinology
☒ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☐ Medical Student ☐Other
Principal Investigator/Mentor: Sangeeta Dhawan
Georgia, Pope Rodnoi, Jalaal Abdul, Mohan Rajkumar
Co-Investigators: Peter C. Butler, Alexandra E. Butler, Senta
Thematic Poster Category: Development, Morphogenesis, Cell Growth and Differentiation, Apoptosis, Stem Cell
Biology, Carcinogenesis and Cancer Biology
Abstract
Both type 1 and type 2 diabetes are caused by loss of functional beta cell mass. Cellular stress in
diabetes induces a progressive loss of beta cell identity, and function, leading to eventual beta cell
loss. Beta cell functional defects in evolving diabetes mimic the behavior of functionally immature beta
cells in neonatal life, marked by an uncoupling of ambient glucose and insulin secretion. This
emphasizes the importance of understanding mechanisms that regulate the functional maturation of
beta cells. Beta cells are formed in embryonic life by differentiation of endocrine progenitors, rapidly
expand by replication, and become functionally mature in late neonatal life. In this study, we identify
Neuropeptide Y (NPY) as a marker of functionally immature beta cell identity in mouse and human
beta cell development. NPY first emerges during embryonic pancreas development and labels subsets
of nascently differentiated endocrine cells in mice and humans. NPY expression in beta cells is
downregulated epigenetically, as these cells become functionally mature and quiescent. This
downregulation is beta cell specific, as NPY persists in mature delta cells. The neonatal NPY positive
beta cell subset is marked by higher replicative capacity. NPY is present in insulin secretory granules
in neonatal beta cells, and knockdown of NPY in neonatal islets improves glucose stimulated insulin
secretion. These data show that NPY expression in neonatal beta cells likely promotes replication and
serves as a break to insulin secretion. We also show that NPY re-emerges in beta cells in diabetes,
coinciding with impaired function, and supports the notion that cellular stress in diabetes leads to loss
of mature beta cell identity and function. Together, these studies establish NPY as a valuable marker
of immature beta cell identity that regulates replication and function, with potential applications to
beta cell regeneration and diabetes therapy.