| Autor: |
Oteng AB; Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.; Center for Research on Genomics and Global Health (CRGGH), National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA., Liu L; Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA., Cui Y; Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA., Gavrilova O; Mouse Metabolism Core., Lu H; Mouse Transgenic Core Facility, NIDDK, NIH, Bethesda, Maryland, USA., Chen M; Signal Transduction Section, Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA., Weinstein LS; Signal Transduction Section, Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA., Campbell JE; Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA., Lewis JE; MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom., Gribble FM; MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom., Reimann F; MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom., Wess J; Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA. |
| Abstrakt: |
Following a meal, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the 2 major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L and K cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K cells. GPCRs couple to 1 or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the α-subunit of Gs, selectively in K cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K cell-specific Gnas-KO mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases. |
