Although GLP-1 is highly biologically active following intravenous or subcutaneous injection, a non-injectable alternative for activating GLP-1 receptor signaling would clearly be desirable. Studies by Gutniak, Ahren and colleagues in Sweden have shown that GLP-1 formulated in buccal tablets is absorbed into the circulation and lowers blood glucose in human subjects. To review the human studies, see GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions. Diabetes Care. 1997 Dec;20(12):1874-9 and Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet. Diabetes Care. 1996 Aug;19(8):843-8
Oral formulations of GLP-1 analogues have also been shown to reduce glycemia excursion in diabetic db/db mice. A microsphere formulation of D-Ala2-GLP-1, a DPP-4-resistant analogue encapsulated in poly(lactide-co-glycolide)-COOH in olive oil, produced a sustained lowering of glycemic excursion in normal and diabetic mice, with glucose levels still significantly lower 8h after microsphere administration. The precise locus for GLP-1 action in these studies is not clear, as levels of insulin, glucagon or rate of gastric emptying was not reported. See Diabetologia 2000 43:1319-1328.
Oral delivery of therapeutic levels of GLP-1 has also been achieved in human subjects. Healthy male volunteers were administered 0.5-4 mg of oral GLP-1, followed by pharmacokinetic assessment of plasma levels of GLP-1over time. Oral GLP-1 increased plasma insulin and suppressed ghrelin, and at the largest dose tested, oral GLP-1 produced a Cmax in plasma of ~220 pM within 20 minutes of oral ingestion Pharmacokinetics and Pharmacodynamic Effects of Oral GLP-1 and PYY3-36: A Proof-of-concept Study in Healthy Subjects Clin Pharmacol Ther. 2008 Mar 26. [Epub ahead of print]
A major challenge for novel delivery systems involves improving the absorption of peptides such as GLP-1 so as to minimize the actual amount of peptide required in various buccal or enteral formulations. Similar comments pertain to current pulmonary peptide delivery systems.
Several groups have used a "gene therapy" approach for sustained therapeutic delivery of GLP-1R agonists in preclinical studies. Systemic delivery of a GLP-1 minigene via an adenovirus improved plasma glucose in both db/d db mice and ZDF rats Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes. Gene Ther. 2006 Aug 24; [Epub ahead of print]
Similarly, intramuscular injection of a hybrid cDNA encoding a GLP-1/Fc peptide normalized glucose tolerance by enhancing insulin secretion and suppressing glucagon release in db/db mice as shown in Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice. Gene Ther. 2006 Aug 31; [Epub ahead of print] and in mice following repeated administration of streptozotocin In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes. Gene Ther. 2007 Apr 5; [Epub ahead of print]
Delivery of GLP-1 via an adenoviral vector was highly effective at controlling blood glucose in ob/ob mice. Ad-GLP-1 normalized blood glucose, improved β-cell function and insulin sensitivity and reduced hepatic glucose production. Remarkably, a single injection of Ad-GLP-1 normalized blood glucose for over 60 days in ob:ob mice-see Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis. Diabetes. 2007 Mar 16; [Epub ahead of print]
Pegylation has also been used to produce stable GLP-1 molecules with longer-acting pharmacokinetic profiles, as described in Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Biochem Pharmacol. 2006 Sep 17;
There is also considerable interest in development of non-peptidic activators of the GLP-1 receptor. Knudsen and colleagues describe the identification of a series of compounds that act as allosteric activators and independent agonists of the GLP-1 receptor. These compounds did not displace GLP-1 binding to the receptor, but did augment GLP-1 binding. The compounds stimulated insulin secretion in islets from wildtype mice but not in islets isolated from Glp1r-/- mice. Furthermore, the compounds enhanced the insulinotropic actions of GLP-1 in experiments using the perfused rat pancreas. See Small-molecule agonists for the glucagon-like peptide 1 receptor Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0605701104
In a related paper, Chen and colleagues describe compounds (non-peptides) that bind to the GLP-1R and increase cyclic AMP formation, actions which are blocked by the GLP-1R antagonist exendin(9-39). One of these compounds, designated Boc5, stimulated glucose-dependent insulin secretion and inhibited food intake in mice, actions that were also blocked by exendin(9-39). Furthermore, repeated administration of Boc5 to db/db mice significantly reduced levels of HbA1c in 6 week experiments. Remarkably, levels of HbA1c remained at values identical to those seen in wildtype animals even 6 weeks after the last dose of the Boc5 compound. See A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0610173104