1775-P: Liraglutide Corrects Impaired Insulin Secretion in 14-3-3-ζ Overexpressing Mice

Crosstalk between α-cells and β-cells is an important regulator of healthy islet function. α-cells display heterogeneity in their hormone profile. α-cells typically produce glucagon but, under certain conditions, can produce glucagon-like peptide-1 (GLP-1). However, the mechanisms regulating α-cell GLP-1 production are poorly understood. We found that increased β-cell GLP-1R signaling via the GLP-1 analog, liraglutide, activates α-cell GLP-1 production through a paracrine signaling pathway. We recently identified the protein 14-3-3-ζ as a key downstream mediator of this pathway. Specifically, liraglutide downregulates β-cell 14-3-3-ζ expression, which activates α-cell GLP-1 production. Consistent with this, we found that β-cell 14-3-3-ζ ablation enhances glucose-stimulated insulin secretion (GSIS). Furthermore, mice with 14-3-3-ζ overexpression (OE) have impaired GSIS. Therefore, we tested the hypothesis that liraglutide can correct the effect of 14-3-3-ζ OE to impair GSIS. Male and female wild-type (WT) or 14-3-3-ζ OE mice maintained on high-fat diet underwent an oral glucose tolerance test (OGTT) after 2 weeks of liraglutide (200 μg/kg sc twice daily) or saline treatment. Liraglutide improved glucose tolerance in WT mice and tended to improve glucose tolerance in OE mice. Saline-treated 14-3-3-ζ OE mice exhibited lower GSIS compared with WT (P<0.05). Liraglutide treatment of 14-3-3-ζ OE mice normalized GSIS to match that of liraglutide-treated WT mice (Insulin secretion index [Insulin AUC/Glucose AUC] *10^-9: Saline WT = 38 ± 4, Lira WT = 37 ± 5, Saline OE = 25 ± 4, Lira OE = 39 ± 7; n=7-8 per group, P<0.05 Saline WT vs. Saline OE, P=0.06 Saline OE vs. Lira OE). Overall, these data suggest that liraglutide can rescue deficits in GSIS induced by 14-3-3-ζ OE.