In:
ChemMedChem, Wiley, Vol. 8, No. 4 ( 2013-04), p. 595-602
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 m M (1.3‐ to 4.9‐fold, p 〈 0.01 to p 〈 0.001) and 16.7 m M 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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201200409
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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