Glucagon like peptide-1 (GLP-1)

GLP-1 is a 30 amino acid peptide (molecular weight of 3297.5) secreted by intestinal L-cells in response to meal ingestion with lipids and carbohydrates. GLP-1 exerts its effect by acting on G-protein-coupled receptors located on the pancreatic P-cells. GLP-1 is strongly insulinotropic in humans, and administration of an antagonist to the GLP-1 receptor, exendin 9-39, in healthy subjects suggests that GLP-1 is essential for normal glucose tolerance in humans. There is a decreased plasma concentration of GLP-1 in T2DM, probably due to an impaired secretion of this incretin hormone. In addition, GLP-1 lowers the gastric emptying, which is often accelerated in patients with T2DM. Furthermore, GLP-1 also exerts its action on pancreatic beta cell by promoting its proliferation and neogenesis. GLP-1 also induces the transformation of non-insulin producing cells into insulin synthesizing cells.

Role of GLP-1 in diabetes management

Recent studies have demonstrated that the GLP-1 can be beneficial in patients with type-1 diabetes mellitus. It has been demonstrated that the GLP-1 administration by subcutaneous injection before meals improves glucose control in typel diabetes. These effects have been attributed to the deceleration of gastric emptying in response to GLP-1. In addition GLP-1 can enhance the differentiation, growth and regeneration of pancreatic P-cells in newly diagnosed typel diabetes patients.

GLP-1 exerts many biological effects. GLP-1 is responsible for a significant part of the insulin response to oral glucose, and both animal and human studies with GLP-1 receptor antagonists suggest that GLP-1 may be essential for normal glucose tolerance. GLP-1 not only enhances insulin secretion but also suppresses the secretion of glucagon in a glucose-dependent fashion. In other words, the suppression of glucagon by GLP-1 does not occur at hypoglycemic plasma glucose concentrations but requires the presence of euglycemia or hyperglycemia.

Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. GLP-1 has been shown to inhibit glucagon secretion in vivo and in vitro. In patients with T2DM, GLP-1 has been proven to reduce glucagon secretion at hyperglycemic condition. Similar to the GLP-1 effects on insulin secretion, GLP-1 has also been shown to affect glucagon secretion only In the presence of high glucose concentration. The exact mechanism of glucagon inhibition is not yet clear. However, it is hypothesized that inhibition of glucagon secretion can be due to direct effect of GLP-1 receptors on islet a-cells or indirect via stimulation of insulin and somatostatin secretion.

Biosynthesis and metabolism of GLP-1

GLP-1 is a product of the proglucagon gene. In the human genome, the proglucagon gene is located on chromosome 17 and spans approximately 10kb. GLP-1, 30 amino acids endogenous proglucagon derived peptide hormone discovered in 1984, is secreted from the intestinal L cells in response to the nutrient ingestion. It has been shown that the posttranslational processing of proglucagon differs in a tissue specific manner. Proprotein convertases (PCs), which are Ca²⁺ dependent serine proteases, have been shown to cleave proprotein and propeptide to generate biologically active peptides in a tissue specific manner. Seven members of the PC family have been identified which includes furin, PC1/3, PC2, PC4, PACE4, PC5/6 and PC7. PC1/3 in the L-cells of gastrointestinal tract has been shown to be responsible for the production of GLP-1 in the intestine. In the alpha cells the proglucagon is processed by PC2 and releases glicentin related polypeptide, glucagon, and some minor and major proglucagon fragment.

GLP-1 Mimetics

Exenatide

A synthetic GLP-1 analogue, Exenatide, is a naturally occurring peptide isolated from the saliva of Gila Lizard (Heloderma Suspectum). It shows better stability in plasma (26 min. after intravenous delivery) and has the same effects as GLP-1. Protease stability of the peptide is due to an Ala→Gly mutation on the penultimate N-terminal amino acid. Exenatide is the first FDA approved peptide drug for treatment of Type II diabetes, and is available since 2005 under the commercial name Byetta. It is administered by two subcutaneous (S.C.) injections per day in 5 to 10µg quantities per injection.

Liraglutide

Liraglutide is a lipidated analogue of GLP-1 with a further extended halflife: 12 hours after I.V. injection. Owing to a lipid tail on Lys24, liraglutide can bind to albumin in plasma and remain in the blood stream in its active form for longer periods of time without proteolysis and clearance, retaining an effect similar to continuous GLP-1 infusion to the plasma. Liraglutide is dosed once daily, S.C., and has been approved by the FDA for treatment of Type II diabetes.

Albiglutide

A longer-lasting analogue, Albiglutide, has been developed as a onceweekly treatment. Considering the advantages of albumin binding for liraglutide, this construct was designed to covalently link albumin to two protease resistant GLP-1 peptides.

Exendin 9-39 and exendin-4 are the most widely used GLP-1 receptor antagonist and agonist, respectively. Since many studies investigating GLP-1 actions use one or both of these peptides, their structure and actions is best described in relation to GLP-1.

Exendin-4 is a 39-aminoacid peptide isolated from the venom of the Gila monster, a poisonous lizard predominantly found in Arizona and New Mexico. Exendin-4 acts as an agonist of the GLP-1 receptor, owing to a 53% sequence homology with GLP-1. Due to the presence of a glycine in position 2 instead of GLP-1’s alanine, exendin-4 is resistant to degradation by DPP IV, and therefore has a longer half-life than GLP-1, making it a good candidate for diabetes therapy.

A fragment of exendin-4, exendin 9-39, has been shown to be a pancreatic GLP-1 receptor antagonist in rats and mice, baboons and humans. The presence of a Trp cage at the C-terminal allows binding to the receptor, but the absence of the N-terminal aminoacids prevents activation of the receptor.

References:

Diren Pamuk, Design and engineering of new glucagonlike-peptide-1 analogues.

Jamaica, Recombinant lactococcus lactis: a novel tool for oral delivery of glucagon like peptide-1 for treatment of type-2 diabetes.