The role of adipose tissue-pancreas cross talk and its implications in metabolic disorders
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Kaja Rupar
Titel
Researcher
Institution
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, United Kingdom
Beløb
DKK 1,050,000
År
2023
Bevillingstype
Visiting Fellowships at University of Oxford
Hvad?
Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose levels and affects approximately 10% of the global adult population, where people with obesity are at a higher risk of developing this metabolic disorder. Current T2DM treatments are unable to regulate blood glucose indefinitely, because pancreatic β-cells, which control glucose by releasing insulin, eventually fail. However, there are other less studied pancreatic islet cell types known to contribute to glucose homeostasis and insulin release including α-cells, which secrete the hormone glucagon. During T2DM these cells become dysregulated, further impairing blood glucose levels and increasing β-cell workload. Therefore, restoration of α-cell function presents a potential therapeutic strategy towards correcting blood glucose levels, relieving β-cell stress and thus slowing down progression of T2DM.
Hvorfor?
It was recently shown that α-cells receive signals from neighboring β-cells as well as the liver, modulating their function. However, not much is known about whether other tissues that regulate glucagon secretion also directly communicate with α-cells. One such tissue is white adipose tissue (WAT), which is crucial for maintaining systemic glucose homeostasis. WAT is a highly secretory organ known to signal to pancreas by releasing factors termed “adipokines”, but it is still unknown whether adipokines directly target α-cells and influence their function (i.e. glucagon secretion). Uncovering adipokines targeting α-cells may present a novel therapeutic venue, enabling extended preservation of α and β-cell function and improvement of T2DM patient outcomes.
Hvordan?
The WAT-secreted factor neuregulin 4 (NRG4) is downregulated with obesity, and is known to bind erb-b2 receptor tyrosine kinase 3 (ERBB3), a receptor highly expressed in α-cells and positively correlated with glucagon secretion. NRG4/ERBB3 signaling thus presents a strong candidate for mediating WAT/α-cell cross talk. To study this metabolic axis in detail, I will produce mice lacking WAT-derived NRG4 as well as mice with α-cell specific ERBB3 knock out. I will then phenotypically characterize mice including body weight, food intake and blood glucose levels, before functionally assessing isolated α-cells using super-resolution imaging techniques and electrophysiological measurement methods.