The SNARE Protein Syntaxin-1a Plays an Essential Role in Biphasic Exocytosis of the Incretin Hormone Glucagon-Like Peptide 1.

Autor:	Wheeler SE; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Stacey HM; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Nahaei Y; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Hale SJ; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Hardy AB; 3D CFI Centre, University of Toronto, Toronto, Ontario, Canada., Reimann F; Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K., Gribble FM; Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K., Larraufie P; Wellcome Trust-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K., Gaisano HY; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.; Department of Medicine, University of Toronto, Toronto, Ontario, Canada., Brubaker PL; Department of Physiology, University of Toronto, Toronto, Ontario, Canada p.brubaker@utoronto.ca.; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2017 Sep; Vol. 66 (9), pp. 2327-2338. Date of Electronic Publication: 2017 Jun 08.
DOI:	10.2337/db16-1403
Abstrakt:	Exocytosis of the hormone glucagon-like peptide 1 (GLP-1) by the intestinal L cell is essential for the incretin effect after nutrient ingestion and is critical for the actions of dipeptidyl peptidase 4 inhibitors that enhance GLP-1 levels in patients with type 2 diabetes. Two-photon microscopy revealed that exocytosis of GLP-1 is biphasic, with a first peak at 1-6 min and a second peak at 7-12 min after stimulation with forskolin. Approximately 75% of the exocytotic events were represented by compound granule fusion, and the remainder were accounted for by full fusion of single granules under basal and stimulated conditions. The core SNARE protein syntaxin-1a (syn1a) was expressed by murine ileal L cells. At the single L-cell level, first-phase forskolin-induced exocytosis was reduced to basal ( P < 0.05) and second-phase exocytosis abolished ( P < 0.05) by syn1a knockout. L cells from intestinal-epithelial syn1a-deficient mice demonstrated a 63% reduction in forskolin-induced GLP-1 release in vitro ( P < 0.001) and a 23% reduction in oral glucose-stimulated GLP-1 secretion ( P < 0.05) in association with impairments in glucose-stimulated insulin release (by 60%; P < 0.01) and glucose tolerance (by 20%; P < 0.01). The findings identify an exquisite mechanism of metered secretory output that precisely regulates release of the incretin hormone GLP-1 and hence insulin secretion after a meal. (© 2017 by the American Diabetes Association.)
Databáze:	MEDLINE
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