Journal
ENDOCRINOLOGY
Volume 163, Issue 9, Pages -Publisher
ENDOCRINE SOC
DOI: 10.1210/endocr/bqac118
Keywords
diurnal; enteroendocrine; GIP; GLP-1; glucose; insulin
Categories
Funding
- Canadian Institutes of Health Research [PJT-14853]
- Ontario Research Fund [19442, 30961]
- Canadian Foundation for Innovation
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Metabolism and circadian rhythms are closely linked, and the secretion of GLP-1 in a rodent model of type 2 diabetes (T2D) increases significantly with a phase shift in peak secretion. The expression of clock genes, SCGN, and insulin release in L-cells is also impaired.
Metabolism and circadian rhythms are intimately linked, with circadian glucagon-like peptide-1 (GLP-1) secretion by the intestinal L-cell entraining rhythmic insulin release. GLP-1 secretion has been explored in the context of obesogenic diets, but never in a rodent model of type 2 diabetes (T2D). There is also considerable disagreement regarding GLP-1 levels in human T2D. Furthermore, recent evidence has demonstrated decreased expression of the beta-cell exocytotic protein secretagogin (SCGN) in T2D. To extend these findings to the L-cell, we administered oral glucose tolerance tests at 6 time points in 4-hour intervals to the high-fat diet/streptozotocin (HFD-STZ) mouse model of T2D. This revealed a 10-fold increase in peak GLP-1 secretion with a phase shift of the peak from the normal feeding period into the fasting-phase. This was accompanied by impairments in the rhythms of glucose, glucagon, mucosal clock genes (Arntl and Cry2), and Scgn. Immunostaining revealed that L-cell GLP-1 intensity was increased in the HFD-STZ model, as was the proportion of L-cells that expressed SCGN; however, this was not found in L-cells from humans with T2D, which exhibited decreased GLP-1 staining but maintained their SCGN expression. Gcg expression in isolated L-cells was increased along with pathways relating to GLP-1 secretion and electron transport chain activity in the HFD-STZ condition. Further investigation into the mechanisms responsible for this increase in GLP-1 secretion may give insights into therapies directed toward upregulating endogenous GLP-1 secretion.
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