(Val8)GLP-1-Glu-PAL: a GLP-1 Agonist That Improves Hippocampal Neurogenesis, Glucose Homeostasis, and β-Cell Function in High-Fat-Fed Mice

This study examined the biological properties of a novel GLP-1 peptide, (Val8)GLP-1-Glu-PAL, engineered with an Ala8Val8 substitution and additional incorporation of a C16 fatty acid moiety at Lys26 via a glutamic acid linker. GLP-1 underwent 75% degradation by DPP-IV over 8h, whereas (Val8)GLP-1 and (Val8)GLP-1-Glu-PAL remained intact. All GLP-1 peptides significantly stimulated insulin secretion at 5.6mM (1.3- to 4.9-fold, p<0.01 to p<0.001) and 16.7mM glucose (1.5- to 2.3-fold, p<0.001). At higher concentrations (Val8)GLP-1-Glu-PAL was significantly more potent at stimulating insulin secretion (1.2- to 1.3-fold, p<0.05). In high-fat-fed mice, all GLP-1 peptides significantly lowered plasma glucose concentrations (4166% decrease, p<0.05 to p<0.001), with (Val8)GLP-1-Glu-PAL eliciting protracted glucose-lowering actions (3259% decrease, p<0.05 to p<0.01) when administered 8h prior to a glucose load. Twice-daily administration of (Val8)GLP-1-Glu-PAL in high-fat-fed mice for 21 days had no effect on bodyweight or food intake, but significantly lowered non-fasting plasma glucose (4346% decrease, p<0.05). (Val8)GLP-1-Glu-PAL markedly decreased glycemic excursion following intraperitoneal glucose (3248% decrease, p<0.05), enhanced insulin response to glucose (2- to 2.3-fold, p<0.05 to p<0.01), and improved insulin sensitivity (2538% decrease in plasma glucose, p<0.05). O2 consumption, CO2 production, RER, and energy expenditure were not altered by (Val8)GLP-1-Glu-PAL therapy. Treatment with (Val8)GLP-1-Glu-PAL resulted in a significant increase in BrdU-positive cells (1.3-fold, p<0.05) in the granule cell layer of the dentate gyrus. These data demonstrate that (Val8)GLP-1-Glu-PAL is a long-acting GLP-1 peptide that significantly improves hippocampal neurogenesis, glucose homeostasis, and insulin secretion in high-fat-fed mice.