BIG3 inhibits insulin granule biogenesis and insulin secretion

Hongyu Li, Shunhui Wei, King Yip Cheng, Natalia V. Gounko, Russell E. Ericksen, Aimin Xu, Wanjin Hong, Weiping Han

Research output: Journal article publicationJournal articleAcademic researchpeer-review

21 Citations (Scopus)

Abstract

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. 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. 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.
Original languageEnglish
Pages (from-to)714-722
Number of pages9
JournalEMBO Reports
Volume15
Issue number6
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Keywords

  • insulin granule biogenesis
  • insulin resistance
  • insulin secretion
  • metabolism
  • proinsulin processing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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