Emma Pepa
Research Mentor: Leslie Satin
Mentor Department: Pharmacology and Brehm Diabetes Center, Medicine
Author(s): Emma Pepa, Dr. Chante Liu, Dr. Leslie Satin
Session: Session 7 (4:00 PM – 4:50 PM)
Presentation Type: Poster 62
Abstract
Type 2 diabetes (T2D) affects over 38 million American adults and is characterized by chronic
hyperglycemia due to insulin resistance and impaired insulin secretion from pancreatic islet beta
cells. The accumulation of toxic islet amyloid polypeptide in the beta cells of patients with
diabetes has been linked to beta cell dysfunction. However, it is not known whether beta cell
hIAPP accumulation alters early islet signaling and beta cell calcium oscillations prior to the
onset of hyperglycemia. To investigate this, we measured the calcium oscillations (an essential
driver of pulsatile insulin secretion) of islets isolated from male transgenic mice expressing
human IAPP (hIAPP). Most of the hIAPP mice became hyperglycemic at 6–9 weeks of age, with
some exhibiting earlier onsets, while FVB control mice remained normal. Pancreatic islets were
isolated and after an overnight culture period, calcium imaging was used to quantify their
glucose-dependent oscillatory properties, including oscillation amplitude, period, and plateau
fraction. Importantly, we detected changes in the free calcium oscillations of islets that were
isolated from hIAPP mice that had not yet exhibited a rise in fasting blood glucose. Our data
support the novel hypothesis that the early increases in islet oscillation amplitude, period, and
plateau fraction may be a compensatory response of beta cells to maintain normal insulin
secretion despite increasing hIAPP toxicity. Over time, however, these properties declined,
indicating decompensation and beta cell dysfunction that likely contributes to the onset of
hyperglycemia. Taken together, these findings may help explain how hIAPP toxicity contributes
to progressive beta cell dysfunction in diabetes. We are currently investigating the molecular
mechanisms that drive this compensatory response. By identifying these early changes may
lead to new treatments to preserve insulin secretion to delay or prevent T2D.
