The role of adipose tissue-pancreas cross talk and its implications in metabolic disorders

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Kaja Rupar




Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, United Kingdom


DKK 1,050,000




Visiting Fellowships at University of Oxford


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.


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.


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.

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