biostudies-literatureLiew CWNIBIB NIH HHSNIDDK NIH HHSFIC NIH HHS2876-88https://www.ebi.ac.uk/biostudies/studies/S-EPMC2912176biostudies-literatureUnknown120(8)Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes (T2DM). Here, we confirm that a previously identified polymorphism (rs2295490/Q84R) in exon 2 of the pseudokinase-encoding gene tribbles 3 (TRB3) is associated with an increased risk for T2DM in 2 populations of people of mixed European descent. Carriers of the 84R allele had substantially reduced plasma levels of C-peptide, the product of proinsulin processing to insulin, suggesting a role for TRB3 in beta cell function. Overexpression of TRB3 84R in mouse beta cells, human islet cells, and the murine beta cell line MIN6 revealed reduced insulin exocytosis, associated with a marked reduction in docked insulin granules visualized by electron microscopy. Conversely, knockdown of TRB3 in MINThe Journal of clinical investigationThe pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells.PMC2912176R03 TW001351P30 DK36836R01 DK082582R01 DK47475R01 DK0474751RL9EB008539-01RL9 EB008539P30 DK036836R01 DK067536R01 DK 67536R01 TW01351Bochenski JKrolewski ASKawamori DQi LWarram JHHu JLeech CAMalecki MKulkarni RNLiew CWWanic KfalseThe pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells.Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes (T2DM). Here, we confirm that a previously identified polymorphism (rs2295490/Q84R) in exon 2 of the pseudokinase-encoding gene tribbles 3 (TRB3) is associated with an increased risk for T2DM in 2 populations of people of mixed European descent. Carriers of the 84R allele had substantially reduced plasma levels of C-peptide, the product of proinsulin processing to insulin, suggesting a role for TRB3 in beta cell function. Overexpression of TRB3 84R in mouse beta cells, human islet cells, and the murine beta cell line MIN6 revealed reduced insulin exocytosis, associated with a marked reduction in docked insulin granules visualized by electron microscopy. Conversely, knockdown of TRB3 in MIN2010-01-01T00:00:00Z2010 Aug2026-04-30T11:23:04.139Z2019-03-27T00:32:47ZS-EPMC29121762059246910.1172/JCI3684910.1172/jci36849