title: Glutamine stimulates biosynthesis and secretion of insulin-like growth factor 2 (IGF2), an autocrine regulator of beta cell mass and function.
abstract: IGF2 is an autocrine ligand for the beta cell IGF1R receptor and GLP-1 increases the activity of this autocrine loop by enhancing IGF1R expression, a mechanism that mediates the trophic effects of GLP-1 on beta cell mass and function. Here, we investigated the regulation of IGF2 biosynthesis and secretion. We showed that glutamine rapidly and strongly induced IGF2 mRNA translation using reporter constructs transduced in MIN6 cells and primary islet cells. This was followed by rapid secretion of IGF2 via the regulated pathway, as revealed by the presence of mature IGF2 in insulin granule fractions and by inhibition of secretion by nimodipine and diazoxide. When maximally stimulated by glutamine, the amount of secreted IGF2 rapidly exceeded its initial intracellular pool and tolbutamide, and high K(+) increased IGF2 secretion only marginally. This indicates that the intracellular pool of IGF2 is small and that sustained secretion requires de novo synthesis. The stimulatory effect of glutamine necessitates its metabolism but not mTOR activation. Finally, exposure of insulinomas or beta cells to glutamine induced Akt phosphorylation, an effect that was dependent on IGF2 secretion, and reduced cytokine-induced apoptosis. Thus, glutamine controls the activity of the beta cell IGF2/IGF1R autocrine loop by increasing the biosynthesis and secretion of IGF2. This autocrine loop can thus integrate changes in feeding and metabolic state to adapt beta cell mass and function.
authors.affiliation: Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Honey
authors.initials: H
authors.lastname: Modi
authors.affiliation: Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Cornu
authors.affiliation: Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland. Electronic address: Bernard.Thorens@unil.ch.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000737:chemistry
chemical_list: C513121:IGF2 protein, mouse; D007328:Insulin; D034741:RNA, Small Interfering; D013453:Sulfonylurea Compounds; D005973:Glutamine; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Beta Cell (B-cell); Glucose; Glutamine; Insulin; Insulin Secretion; Insulin-like Growth Factor (IGF)