title: (Val(8))GLP-1-Glu-PAL: a GLP-1 agonist that improves hippocampal neurogenesis, glucose homeostasis, and β-cell function in high-fat-fed mice.
abstract: This study examined the biological properties of a novel GLP-1 peptide, (Val(8))GLP-1-Glu-PAL, engineered with an Ala(8)→Val(8) substitution and additional incorporation of a C(16) fatty acid moiety at Lys(26) via a glutamic acid linker. GLP-1 underwent 75 % degradation by DPP-IV over 8 h, whereas (Val(8))GLP-1 and (Val(8))GLP-1-Glu-PAL remained intact. All GLP-1 peptides significantly stimulated insulin secretion at 5.6 mM (1.3- to 4.9-fold, p<0.01 to p<0.001) and 16.7 mM glucose (1.5- to 2.3-fold, p<0.001). At higher concentrations (Val(8))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 (41-66 % decrease, p<0.05 to p<0.001), with (Val(8))GLP-1-Glu-PAL eliciting protracted glucose-lowering actions (32-59 % decrease, p<0.05 to p<0.01) when administered 8 h prior to a glucose load. Twice-daily administration of (Val(8))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 (43-46 % decrease, p<0.05). (Val(8))GLP-1-Glu-PAL markedly decreased glycemic excursion following intraperitoneal glucose (32-48 % 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 (25-38 % decrease in plasma glucose, p<0.05). O(2) consumption, CO(2) production, RER, and energy expenditure were not altered by (Val(8))GLP-1-Glu-PAL therapy. Treatment with (Val(8))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 (Val(8))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.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Lennox
authors.forename: David W
authors.initials: DW
authors.lastname: Porter
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D015195:Drug Design; D004734:Energy Metabolism / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D055495:Neurogenesis / Q000187:drug effects*
chemical_list: C583431:(Val8)GLP-1-Glu-PAL; D001786:Blood Glucose; D007328:Insulin; D055666:Lipopeptides; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4