Impact of pregnancy, diet, age and gender on the morphology and function of the pancreatic islets

Abstract

The modulation of pancreatic islet cell morphology and function is frequently associated with environmental factors such as pregnancy, diet, age and sex. This link has been demonstrated across species including humans in both non-diabetic and diabetic models. The present thesis examines the impact of these challenges over time on pancreatic islet cell morphology and functional activity. This was studied in wild- type C57BL/6 mice and transgenic animals with islet cell-specific expression of f luorescent reporters, using immunohistochemistry and real-time imaging of intracellular metabolism and signalling. We report that pregnancy increased insulin producing beta cell mass, number, neogenesis and transdifferentiation rate from non/ endocrine cells such as ductal and alpha cells, arguably to overcome insulin resistance. This was accompanied by elevated insulin secretion, accomplished via potentiation of intracellular pathways such as glycolysis, oxidative metabolism and Ca2+ dynamics, in pregnant mice islets. However, consumption of a high-fat (‘cafeteria’) diet blocked these pregnancy-induced changes with increased beta cell apoptosis. Insulin secretion and associated intracellular pathways were likewise impaired in islets chronically cultured in glucolipotoxic conditions. Islet cell biology and function were affected similarly in mice that had two or three pregnancies, thereby demonstrating resilience of the adaptive mechanisms. Further to this, male mice displayed adaptive pancreatic responses to ageing, including an attenuation of pancreatic islet cell function, beta cell proliferation, number and mass, alongside decreased transdifferentiation from alpha and ductal cells. Notably, young male mice exhibited higher islet beta cell area and reduced beta cell apoptosis alongside x enhanced alpha-/ ductal- to- beta-cell transdifferentiation compared to age-matched female mice. This morphological superiority was lost in male mice with age, suggesting greater pancreatic adaptivity in old females with a decreased risk of diabetes. Overall, these results indicate important interlinked effects of pregnancy, age and gender on pancreatic islet morphology and function, arguably reflected by changes in hormonal output. Greater understanding of how these factors act synergistically could benefit beta cell restoration strategies and provide novel therapeutic options for diabetes therapy.

Thesis is embargoed until 31st May 2027

Date of Award	May 2025
Original language	English
Supervisor	Neil Tanday (Supervisor), Peter Flatt (Supervisor), Charlotte Moffett (Supervisor) & Andrei Tarasov (Supervisor)