GLP-1/GLP-1R: The Star Target for Type 2 Diabetes Mellitus Treatment

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronically elevated blood glucose levels. It typically results from inadequate insulin secretion because of dysfunction of the insulin-secreting pancreatic beta cells. At present, several oral antidiabetic medications are used for the treatment of T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists (GLP-1RAs), peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium–glucose transporter 2 (SGLT2) inhibitors. In recent years, GLP-1RAs have become well-established therapies in T2DM.

GLP-1/GLP-1RA and derived metabolites

The active form of GLP-1 is GLP-1(7–36) amide, which represents a major secretory product. However, the native GLP-1 peptide does not seem to be suitable for long-term treatment of patients with type 2 diabetes mellitus, primarily owing to its low stability in vivo.

GLP-1RA

GLP-1 therapies have been established using two main approaches: DPP4-resistant GLP-1 agonists/GLP-1RA and DPP-4 inhibitors, both of which aim to prolong the life-time of circulating GLP-1(7–36) amide. GLP-1RAs are useful tools for the treatment of T2DM, especially for patients aiming weight loss or to hypoglycaemia.

Fig. 2 Strategies employed to develop GLP-1 receptor agonists with prolonged in vivo half-lives. (Meier JJ. Nat Rev Endocrinol. 2012)

• Exenatide

Exenatide has 53% homology with GLP-1. It has a strong binding ability to GLP-1 receptor and is not easily degraded by DPP-4. Following peripheral administration, exenatide has been shown to suppress food intake via vagal-dependent and vagal-independent pathways that result in the direct activation of GLP-1R in the central nervous system.

• Liraglutide

Liraglutide is derived from human GLP-1-(7-37), and it has 97% amino acid homology to endogenous human GLP-1. With a fatty-acyl moiety on the GLP-1 peptide backbone, it has an increased half-life as a result of DPP-4 resistance and non-covalent binding to serum albumin.

• Albiglutide

Albiglutide is a long-acting GLP-1RA. Amino acids 1–30 and 31–60 constitute two copies of modified human GLP-1, the alanine at position 2 having been exchanged for a glycine for better DPP-4 resistance.

• Semaglutide

Semaglutide has 31 amino-acid containing peptidic structure which is 94% homologous to the native GLP-1 for avoiding immunogenicity. It is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1 receptor agonist).

DPP-4 inhibitors

DPP-4 inhibitors have broad therapeutic applicability. To date, several small molecule DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, lina-gliptin, and alogliptin) have been used as treatments for type 2 diabetes to improve glucose tolerance. In addition, studies have shown that DDP-4 vaccines and inhibitory anti-DDP-4 antibody also have therapeutic potential due to their ability to improve glucose metabolism in mice.