Date of Award
Doctor of Philosophy (PhD)
Pancreatic β-cells perform glucose-stimulated insulin secretion, a process required to maintain systemic glucose homeostasis. Obesity promotes glycemic and inflammatory stress, causing β-cell death and dysfunction, resulting in diabetes. Efforts to improve β-cell function in obesity have been hampered by observations that β-cells are highly heterogeneous, varying in morphology, function, and gene expression. There is great need to understand the breadth of β-cell heterogeneity in health and obesity to improve diabetic therapies.High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we show that as they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. Next, we integrate pancreatic islet single cell and bulk RNA sequencing data to identify β-cell subpopulations based on gene expression and characterize genetic networks associated with β-cell function in obese SM/J mice. We assign roles to 4 β-cell subpopulations, whose composition is influenced by age, sex, and diet. Network analysis identified fatty acid metabolism and β-cell physiology gene expression modules associated with the hyperglycemic-obese state. We identify subtype-specific expression of Pdyn and Fam151a as candidate regulators of β-cell function in obesity. These results establish that improved β-cell function underlies the resolution of hyperglycemia, which may be driven by changes in subpopulation structure and decreased fatty acid metabolism.
Chair and Committee
Heather A. Lawson
Jing Hughes, Jeffery Millman, David Piston, Maria Remedi,
Miranda, Mario Alejandro, "Exploring β-cell Function and Heterogeneity in Obese SM/J Mice" (2021). Arts & Sciences Electronic Theses and Dissertations. 2515.