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Alternative GLP-1 Delivery Systems

Although glucagon-like peptide-1 (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.1-2

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. 3

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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-1 over 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.4

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. Ye and colleagues used synthetic biology (combing melanopsin and NFAT regulatory elements) to enable transgene and light-directed control of a GLP-1 minigene, under the control of a light sensitive promoter, in transfected HEK-293 cells, in both normal and diabetic mice. Light pulses increased GLP-1 production, plasma GLP-1 levels and enhanced glucose-stimulated insulin secretion and glucose homeostasis.5

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.6

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 and in mice following repeated administration of streptozotocin.7-8

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.9

Pegylation has also been used to produce stable GLP-1 molecules with longer-acting pharmacokinetic profiles, as described.10

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.11

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.12

Sloop and colleagues generated a series of small molecule GLP-1R agonists that activated cAMP formation in cells expressing a transfected GLP-1R; intriguingly, the classical GLP-1R antagonist exendin(9-39) did not block the actions of these compounds on the GLP-1R and the compounds did not displaced iodinated GLP-1 binding on GLP-1R+ cell membranes. Furthermore, the small molecule agonists, but not native GLP-1, could still activated an N-terminally truncated GLP-1R lacking the first 138 amino acids at the N-terminus. Compound B also increases GSIS from perfused rat islets in vitro, and stimulated the GLP-1R in an additive manner when co-incubated with []s of native GLP-1. Compound B given intravenously also activated GSIS in rats in vivo and stimulated insulin secretion from perifused human islets.13

  1. GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions. Diabetes Care. 1997 Dec;20(12):1874-9
  2. Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet. Diabetes Care. 1996 Aug;19(8):843-8
  3. Diabetologia 2000 43:1319-1328.
  4. 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]
  5. A Synthetic Optogenetic Transcription Device Enhances Blood-Glucose Homeostasis in Mice Science 24 June 2011: 1565-1568
  6. Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes. Gene Ther. 2006 Aug 24; [Epub ahead of print]
  7. 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]
  8. 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]
  9. 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]
  10. 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;
  11. Small-molecule agonists for the glucagon-like peptide 1 receptor Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0605701104
  12. 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
  13. Novel Small Molecule Glucagon-like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and from Human Islets Diabetes. 2010 59(12):3099-107.

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