Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes

Jul 25, 2022Endocrinology

Changes and Higher Daily Levels of a Blood Sugar-Regulating Hormone in a Mouse Model of Type 2 Diabetes

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Abstract

A 10-fold increase in peak GLP-1 secretion was observed in a mouse model of type 2 diabetes.

The peak GLP-1 secretion shifted from the normal feeding period to the fasting phase in the high-fat diet/streptozotocin mouse model.
Impairments in glucose, glucagon, and mucosal clock gene rhythms were noted alongside the altered GLP-1 secretion.
Increased L-cell GLP-1 intensity and a higher proportion of L-cells expressing the protein secretagogin were found in the HFD-STZ model.
In contrast, human L-cells with type 2 diabetes showed decreased GLP-1 staining while maintaining SCGN expression.
Gcg expression and pathways related to GLP-1 secretion and electron transport chain activity were increased in isolated L-cells from the HFD-STZ condition.

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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 β-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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Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes

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