Hongyu Li1,2, Shunhui Wei2, Kenneth Cheng3,4, Natalia V Gounko1,5, Russell E Ericksen2, Aimin Xu3,4,6, Wanjin Hong*,1 and Weiping Han*,2
1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
2 Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
3 State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
4 Department of Medicine, University of Hong Kong, Hong Kong, China
5 Joint IMB‐IMCB Electron Microscopy Suite, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
6 Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China
* Corresponding author
Published online in EMBO Reports on 7 April 2014.
While molecular regulation of insulin granule exocytosis is relatively well understood, insulin granule biogenesis and maturation and its influence on glucose homeostasis are relatively unclear. Here, we identify a novel protein highly expressed in insulin‐secreting cells and name it BIG3 due to its similarity to BIG/GBF of the Arf‐GTP exchange factor (GEF) family. BIG3 is predominantly localized to insulin‐ and clathrin‐positive trans‐Golgi network (TGN) compartments. BIG3‐deficient insulin‐secreting cells display increased insulin content and granule number and elevated insulin secretion upon stimulation. Moreover, BIG3 deficiency results in faster processing of proinsulin to insulin and chromogranin A to β‐granin in β‐cells. BIG3‐knockout mice exhibit postprandial hyperinsulinemia, hyperglycemia, impaired glucose tolerance, and insulin resistance. Collectively, these results demonstrate that BIG3 negatively modulates insulin granule biogenesis and insulin secretion and participates in the regulation of systemic glucose homeostasis.
Figure legend: Synopsis
This study identifies a regulatory role for the novel protein BIG3 in systemic metabolism through its inhibitory effects on insulin granule biogenesis and insulin secretion.
· BIG3 is associated with immature insulin granules in pancreatic β‐cells.
· BIG3 restricts prohormone processing and insulin granule biogenesis.
· BIG3 deficiency results in elevated insulin content and insulin secretion.
· BIG3‐knockout mice show postprandial hyperglycemia and insulin resistance.
For more information on Weiping HAN’s laboratory, please click here.
For more information on Wanjin HONG’s laboratory, please click here.