title: Pim3 negatively regulates glucose-stimulated insulin secretion.
abstract: Pancreatic β-cell response to glucose stimulation is governed by tightly regulated signaling pathways which have not been fully characterized. A screen for novel signaling intermediates identified Pim3 as a glucose-responsive gene in the β cell, and here, we characterize its role in the regulation of β-cell function. Pim3 expression in the β-cell was first observed through microarray analysis on glucose-stimulated murine insulinoma (MIN6) cells where expression was strongly and transiently induced. In the pancreas, Pim3 expression exhibited similar dynamics and was restricted to the β cell. Perturbation of Pim3 function resulted in enhanced glucose-stimulated insulin secretion, both in MIN6 cells and in isolated islets from Pim3-/- mice, where the augmentation was specifically seen in the second phase of secretion. Consequently, Pim3-/- mice displayed an increased glucose tolerance in vivo. Interestingly, Pim3-/- mice also exhibited increased insulin sensitivity. Glucose stimulation of isolated Pim3-/- islets resulted in increased phosphorylation of ERK1/2, a kinase involved in regulating β-cell response to glucose. Pim3 was also found to physically interact with SOCS6 and SOCS6 levels were strongly reduced in Pim3-/- islets. Overexpression of SOCS6 inhibited glucose-induced ERK1/2 activation, strongly suggesting that Pim3 regulates ERK1/2 activity through SOCS6. These data reveal that Pim3 is a novel glucose-responsive gene in the β cell that negatively regulates insulin secretion by inhibiting the activation of ERK1/2, and through its effect on insulin sensitivity, has potentially a more global function in glucose homeostasis.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Vlacich
authors.forename: Martijn C
authors.initials: MC
authors.lastname: Nawijn
authors.forename: Gene C
authors.initials: GC
authors.lastname: Webb
authors.forename: Donald F
authors.initials: DF
authors.lastname: Steiner
mesh_terms: D000818:Animals; D002460:Cell Line; D048429:Cell Size; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006943:Hyperglycemia; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C473086:Socs6 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C488192:Pim3 protein, mouse; D017346:Protein Serine-Threonine Kinases