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RNA-binding protein PCBP2 regulates pancreatic [beta] cell function and adaptation to glucose

Authors :
Haemmerle, Matthew W.
Scota, Andrea V.
Khosravifar, Mina
Varney, Matthew J.
Sen, Sabyasachi
Good, Austin L.
Yang, Xiaodun
Wells, Kristen L.
Sussel, Lori
Rozo, Andrea V.
Doliba, Nicolai M.
Ghanem, Louis R.
Stoffers, Doris A.
Source :
Journal of Clinical Investigation. June 15, 2024, Vol. 134 Issue 12
Publication Year :
2024

Abstract

Introduction Glucose uptake and metabolism are the most physiologically important driver of insulin release from pancreatic islet [beta] cells, a highly specialized class of endocrine cells that secrete this hormone [...]<br />Glucose plays a key role in shaping pancreatic [beta] cell function. Thus, deciphering the mechanisms by which this nutrient stimulates [beta] cells holds therapeutic promise for combating [beta] cell failure in type 2 diabetes (T2D). [beta] cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the mechanisms governing these changes remain poorly understood. Here, we identify a requirement for the RNA-binding protein PCBP2 in maintaining [beta] cell function basally and during sustained hyperglycemic challenge. PCBP2 was induced in primary mouse islets incubated with elevated glucose and was required to adapt insulin secretion. Transcriptomic analysis of primary Pcbp2-deficient [beta] cells revealed impacts on basal and glucose-regulated mRNAs encoding core components of the insulin secretory pathway. Accordingly, Pcbp2-deficient [beta] cells exhibited defects in calcium flux, insulin granule ultrastructure and exocytosis, and the amplification pathway of insulin secretion. Further, PCBP2 was induced by glucose in primary human islets, was downregulated in islets from T2D donors, and impacted genes commonly altered in islets from donors with T2D and linked to single-nucleotide polymorphisms associated with T2D. Thus, these findings establish a paradigm for PCBP2 in governing basal and glucose-adaptive gene programs critical for shaping the functional state of [beta] cells.

Details

Language :
English
ISSN :
00219738
Volume :
134
Issue :
12
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.801951048
Full Text :
https://doi.org/10.1172/JCI172436