Structural and functional changes of the endocrine pancreas under conditions of beta cell stress and pregnancy

Abstract

Diabetes Mellitus, also known as diabetes, is a chronic metabolic disease characterized by high blood glucose levels for an extended period of time, which can cause serious problems if not correctly managed. However, under special circumstances, some cases of diabetes can regress. The overall objective of this study was to investigate if metabolic adaptations (such as rapid weight loss/gain, extreme blood glucose fluctuations, and pregnancy) cause any structural alterations to the pancreatic islets, particularly islet beta cells. Studies have already shown that the islet cells, such as alpha and beta cells, undergo many alterations under metabolic stress, most notably islet cell mass expansion. The exact underlying mechanism/s of this expansion is unknown. However, there is a hypothesis that stress can induce islet beta cell transdiferentiation into alpha cells (and vice versa), and that this process can be reversed when the stressor is removed. To examine this two islet cell lineage tracing mouse strains Ins1Cre/+;Rosa26-eYFP (InsCre) and GluCreERT2;ROSA26-eYFP (GluCre) were employed with observations on islet architecture and cell identity made in pregnant and post pregnant mice. These studies demonstrated that the significant islet cell expansion in pregnancy is driven by alpha and beta transdifferentiation and de-deffrentiation, as well as possible islet cell neogenesis, and fission. Furthermore, pancreatic islets do revert to more normal morphology post-pregnancy. Additional studies on obese Zucker diabetic fatty (ZDF) rats show that gastric Roux-en-Y (RYN) surgery, as well as standard of care treatment intervention, also effects islet morphology. As such, RYN rats that have undergone the medical treatment after surgery show a regression in islet size and lower blood glucose level. Together, these studies provide insight into the role of alterations of islet cell lineage under metabolic stress.

Date of Award	Sept 2024
Original language	English
Supervisor	Victor Gault (Supervisor) & Nigel Irwin (Supervisor)