A Recombinant Human Glucagon-Like Peptide (GLP)-1–Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor–Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis

Aug 28, 2004Diabetes

A lab-made GLP-1-albumin protein mimics natural signals that control fullness, digestion, and blood sugar

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Abstract

Albugon, a human glucagon-like peptide-1-albumin recombinant protein, activates GLP-1 receptors with an EC(50) of 0.2 nmol/l, significantly lower than the agonist exendin-4.

Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type mice.
The effects of Albugon were not observed in GLP-1 receptor-deficient mice.
Albugon reduced food intake after administration through different routes, including intracerebroventricular and intraperitoneal.
Intraperitoneal injection of Albugon inhibited gastric emptying.
Albugon activated c-FOS expression in several brain regions associated with energy intake and glucose regulation.

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Peptide hormones exert unique actions via specific G protein-coupled receptors; however, the therapeutic potential of regulatory peptides is frequently compromised by rapid enzymatic inactivation and clearance from the circulation. In contrast, recombinant or covalent coupling of smaller peptides to serum albumin represents an emerging strategy for extending the circulating t(1/2) of the target peptide. However, whether larger peptide-albumin derivatives will exhibit the full spectrum of biological activities encompassed by the native peptide remains to be demonstrated. We report that Albugon, a human glucagon-like peptide (GLP)-1-albumin recombinant protein, activates GLP-1 receptor (GLP-1R)-dependent cAMP formation in BHK-GLP-1R cells, albeit with a reduced half-maximal concentration (EC(50)) (0.2 vs. 20 nmol/l) relative to the GLP-1R agonist exendin-4. Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type but not GLP-1R(-/-) mice and reduced food intake after both intracerebroventricular and intraperitoneal administration. Moreover, intraperitoneal injection of Albugon inhibited gastric emptying and activated c-FOS expression in the area postrema, the nucleus of the solitary tract, the central nucleus of the amygdala, the parabrachial, and the paraventricular nuclei. These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo.

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A Recombinant Human Glucagon-Like Peptide (GLP)-1–Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor–Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis

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