BIG3 inhibits insulin granule biogenesis and insulin secretion.
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.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Hongyu
H
Li
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Shunhui
S
Wei
State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China Department of Medicine, University of Hong Kong, Hong Kong, China.
Kenneth
K
Cheng
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore Joint IMB-IMCB Electron Microscopy Suite, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Natalia V
NV
Gounko
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Russell E
RE
Ericksen
State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China Department of Medicine, University of Hong Kong, Hong Kong, China Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
Aimin
A
Xu
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore weiping_han@sbic.a-star.edu.sg mcbhwj@imcb.a-star.edu.sg.
Wanjin
W
Hong
Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore weiping_han@sbic.a-star.edu.sg mcbhwj@imcb.a-star.edu.sg.
Weiping
W
Han
D000818:Animals; D002153:Calorimetry, Indirect; D005947:Glucose / Q000502:physiology; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000737:chemistry*; D021601:trans-Golgi Network / Q000378:metabolism
D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C443118:Wdr5 protein, mouse; D005947:Glucose
insulin granule biogenesis; insulin resistance; insulin secretion; metabolism; proinsulin processing