The Effects of Evolution and Associated Differences in Dietary Preferences on Pancreas Architecture and Islet Function

University Of California At Davis, Davis CA

Investigators

Abstract

The importance of differences in islet architecture between rodent and human islets is much debated and remains understudied, highlighting a need to further understand the relationship between islet architecture and function. A large-scale comparative approach to characterize species differences at the morphological and functional levels can provide important context to variations observed between rodent and human islet physiology. Although evolutionary changes may contribute to broader differences in islet architecture across distantly related species, they do not explain differences in pancreas architecture between closely related species. These variations may instead be attributed to differences in diet and metabolism. This is supported by evidence that even individual increases in metabolic demand are associated with architectural changes within the islet. This has informed the hypothesis that species-specific variations in metabolism and dietary composition influence pancreas architecture and function in addition to phylogenetic relatedness. Reports of islet architecture have been described for some species, but these data are based on the assessment of a limited number of islets, often from a single animal for a relatively limited number of species. This gap will be addressed by utilizing a systematic, high-throughput comparative approach to quantify pancreas architecture differences across species and correlating these changes to functional differences at the cellular level in response to variations in macronutrient stimulation. The study of species with alterations in their reliance of various macronutrients, namely glucose, provides a unique opportunity to explore the role of α and β cells as nutrient sensors of the islet. Aim 1 will systematically quantify variations in morphology and paracrine factors using high-throughput image analysis across carefully selected samples from unique collection of 11,000 pancreas samples representing all major vertebrate taxa banked at the UC Davis School of Veterinary Medicine. Aim 2 will compare rodent and human Ca2+ and cAMP dynamics to those of live pancreatic slices from carnivores and ruminants, whose unique dietary and metabolic adaptations favor a constant gluconeogenic state. These approaches are innovative as they employ a systematic, quantitative approach to understand islet architecture and function through a comparative lens. These proposed aims are significant as they will provide an understanding of how variations in islet architecture correlate with the macronutrient sensitivity of α and β cells within the islet. This foundational knowledge may prove essential to understanding the consequences of islet architectural defects on dysregulated hormone secretion in human diabetes.