Dissertation
The impact of a pancreatic micropeptide in insulin homeostasis under obese and diabetic conditions
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
Abstract
Diabetes mellitus is among the most common chronic diseases, affecting more than 1 in 10 Americans with about 1.5 million new cases diagnosed each year. Pancreatic beta cell dysfunction is a key factor in numerous forms of diabetes, including Type 1, Type 2, and Cystic Fibrosis-Related Diabetes. There remains a critical need to understand what causes beta cell dysfunction and to establish therapeutic targets to correct it. Micropeptides encoded by transcripts previously annotated as long noncoding RNA (IncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Our prior work identified a beta cell-enriched lncRNA-encoded micropeptide, Beta cell- and Neural cell-regulin (BNLN), and demonstrated its critical role in pancreatic beta cell function and insulin secretion. Here, we investigated the spatiotemporal expression of endogenous BNLN in the healthy and diseased pancreas. We further sought to identify its functional significance and factors driving changes in its abundance. We find that BNLN primarily localizes to the beta cell in the healthy pancreas, with alterations in abundance and distribution in diabetes through the use of human samples and ferret and mouse models of diabetes. To determine the cell type-specific role of BNLN, we establish a beta cell-specific BNLN knockout mouse model and demonstrate in vivo loss of glycemic control under diet-induced obese conditions These changes are more limited in a lean knockout model. In vitro, we show that a wide array of disease-relevant beta cell stressors drive increased endogenous expression of BNLN and its encoding RNA TUNAR. Collectively, these results establish critical importance for pancreatic micropeptides in maintaining metabolic homeostasis in disease and other challenged states, advancing our understanding of beta cell regulation and stress response mechanisms for the maintenance of systemic function. These results provide a foundation for future comprehensive analyses of micropeptide functions and their pathophysiological impact on diabetes.
Details
- Title: Subtitle
- The impact of a pancreatic micropeptide in insulin homeostasis under obese and diabetic conditions
- Creators
- Tate Neff
- Contributors
- Ling Yang (Advisor)Andrew Norris (Committee Member)Brandon Davies (Committee Member)John F Engelhardt (Committee Member)Samuel Stephens (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cell and Developmental Biology)
- Date degree season
- Spring 2026
- Publisher
- University of Iowa
- Number of pages
- xvi, 174 pages
- Copyright
- Copyright 2026 Tate Neff
- Language
- English
- Date submitted
- 04/27/2026
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (page 152-174).
- Public Abstract (ETD)
Controlling blood sugar is a vital part of maintaining health and providing energy to tissues that need it. When the body is unable to control blood sugar, through secretion and sensing of the hormone insulin, diabetes results. There are several forms of diabetes, including Type 1 Diabetes, from autoimmune attack against the cells producing insulin, Type 2 Diabetes, from the body’s inability to respond normally to insulin, and Cystic Fibrosis-Related Diabetes, a combination of both problems downstream of a genetic mutation causing cystic fibrosis. Altogether, diabetes is among the most common chronic diseases, and treatment options are limited. Our group previously identified a small protein, called BNLN, which allows insulin-producing cells to more easily secrete that insulin into the bloodstream. The goal of my thesis work is to understand where in the pancreas that protein naturally exists in health and disease, to uncover whether it is necessary to maintain control of blood sugar, and to determine what factors manipulate how much or little of it is produced.
To this end, I have stained the protein in pancreatic tissue from humans, ferrets, and mice in both health and disease, finding that it is mostly located in the insulin-producing cells, but is also expressed in other pancreatic cell types. Under some of the disease conditions I examined, the protein is enriched. We also developed a mouse model with obesity and a genetic mutation to remove the protein from insulin-producing cells, and found that these mice are unable to secrete enough insulin to lower their blood sugar after a sugar injection. This indicates that the protein is necessary to control blood sugar in disease conditions. Finally, we used insulin-producing cells treated with several stressors, including sugar, fats, and inflammation-promoting chemicals, finding that expression of the protein and the gene that creates it are enriched. We also identified expression of the protein in areas of the pancreas that do not produce hormones, opening new areas of interest for future research into its role there. Together, the research here clarifies the role of this small protein in insulin-producing cells of the pancreas, its expression, and its regulation. This helps to lay the groundwork for future development of therapies for diabetes, and highlights the importance of studying similar proteins in the pancreas.
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9985177271002771
Metrics
1 Record Views