1193-P: Investigating the Role of Intestinal L-Cell Secretagogin in Circadian GLP-1 Secretion in a Mouse Model of Type 2 Diabetes

The intestinal L-cell hormone Glucagon-like Peptide-1 (GLP-1) increases glucose-dependent insulin secretion and is thus used in the treatment of T2D. GLP-1 secretion from the L-cell exhibits a circadian pattern in rodents and varies by time-of-day in humans. We have shown that KD of the SNARE-regulatory protein, secretagogin (SCGN) prevents time-dependent GLP-1 release. SCGN KD in ß-cells also decreases insulin secretion and SCGN levels are reduced in T2D islets. We thus hypothesized that SCGN is decreased in the L-cell in T2D, causing alterations in the physiological pattern of GLP-1 secretion. High-fat diet, low-dose streptozotocin (HFD-STZ) mice, a model of T2D, exhibited increased fasting glucose (5.5 vs. 15.6 mmol/L; p<0.001) and decreased ß-cell area (by 75%, p<0.001). Unexpectedly, oral glucose tolerance tests conducted in 4-hour intervals through the 24-hr day showed that HFD-STZ mice exhibit a 10x increase in GLP-1 responses (400 vs. 4000 pg/ml*60 min, p<0.001) and exhibit an anti-phasic rhythm to controls. Basal GLP-1 levels remained unchanged between HFD-STZ and controls. Unexpectedly, insulin responses were not reduced in HFD-STZ mice, suggesting that increased GLP-1 levels could act as a compensatory mechanism. HFD-STZ mice also exhibited hyperglucagonemia compared to control, with increased glucagon secretion across timepoints following glucose administration (–243 vs. 800 pg/ml*60 min, p<0.001). RT-qPCR of intestinal mucosa showed an anti-phasic Scgn rhythm in the HFD-STZ model, with a 1.5-fold increase in average expression across timepoints (p<0.05), which could explain the drastically increased GLP-1 secretion. These data show that GLP-1 secretion is both increased and arrhythmic in a murine model of T2D, and that this occurs in association with an unanticipated increase in Scgn expression. Further investigation into the role of SGCN in the L-cell may serve as an avenue for therapeutics aimed at increasing endogenous GLP-1 release.