The hormone glucagon-like peptide-1(736)amide (GLP-1) is released in response to ingested nutrients and acts
to promote glucose-dependent insulin secretion ensuring
efficient postprandial glucose homeostasis. Unfortunately,
the beneficial actions of GLP-1 which give this hormone
many of the desirable properties of an antidiabetic
drug are short lived due to degradation by dipeptidylpeptidase
IV (DPP IV) and rapid clearance by renal filtration.
In this study we have attempted to extend GLP-1
action through the attachment of palmitoyl moieties to
the ?amino group in the side chain of the Lys26 residue and to combine this modification with substitutions of the
Ala8 residue, namely Val or aminobutyric acid (Abu). In
contrast to native GLP-1, which was rapidly degraded,
[Lys(pal)26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys(pal)26]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor
binding affinity and the ability to increase cyclic AMP in
the clonal ?cell line BRINBD11 were decreased by 86-
to 167-fold and 15- to 62-fold, respectively compared
with native GLP-1. However, insulin secretory potency
tested using BRINBD11 cells was similar, or in the case
of [Val8,Lys(pal)26]GLP-1 enhanced. Furthermore, when
administered in vivo together with glucose to diabetic
(ob/ob) mice, [Lys(pal)26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys(pal)26]GLP-1 did not demonstrate acute
glucoselowering or insulinotropic activity as observed
with native GLP-1. These studies support the potential
usefulness of fatty acid linked analogues of GLP-1 but
indicate the importance of chain length for peptide kinetics and bioavailability.
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Biological Chemistry keeps you up-to-date with the latest advances in the molecular life sciences. The journal publishes Research Articles, Short Communications, Reviews and Minireviews. Areas include: general biochemistry/pathobiochemistry, structural biology, molecular and cellular biology, genetics and epigenetics, virology, molecular medicine, plant molecular biology/biochemistry and novel experimental methodologies.