Abstract
The intestinal L-cell incretin, glucagon-like peptide-1 (GLP-1), exhibits a circadian pattern of secretion, thereby entraining diurnal insulin release. Secretagogin (Scgn), an actin-binding regulatory protein, is essential for the temporal peak of GLP-1 secretion in vitro. To interrogate the role of Scgn in diurnal GLP-1 secretion in vivo, peak and trough GLP-1 release were evaluated in knockout mice (Scgn-/-, Gcg-CreERT2/+; Scgnfl/fl and Vil-CreERT2/+; Scgnfl/fl), and RNA sequencing (RNA-Seq) was conducted in Scgn knockdown L-cells. All 3 knockout models demonstrated loss of the diurnal rhythm of GLP-1 secretion in response to oral glucose. Gcg-CreERT2/+; Scgnfl/fl mice also lost the normal pattern in glucagon secretion, while Scgn-/- and Vil-CreERT2/+; Scgnfl/fl animals demonstrated impaired diurnal secretion of the related incretin, glucose-dependent insulinotrophic polypeptide. RNA-Seq of mGLUTag L-cells showed decreased pathways regulating vesicle transport, transport and binding, and protein-protein interaction at synapse, as well as pathways related to proteasome-mediated degradation including chaperone-mediated protein complex assembly following Scgn knockdown. Scgn is therefore essential for diurnal L-cell GLP-1 secretion in vivo, likely mediated through effects on secretory granule dynamics.
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