Glucagon-like peptide 1

Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon gene. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 composes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

Alongside glucose-dependent insulinotropic peptide (GIP), GLP-1 is the only known incretin describing its ability to decrease blood sugar levels in a glucose-dependent manner by enhancing the secretion of insulin. Beside the insulinotropic effects, GLP-1 has been associated with numerous regulatory and protective effects. Unlike GIP, the action of GLP-1 is preserved in patients with type 2 diabetes and substantial pharmaceutical research has therefore been directed towards the development of GLP-1-based treatment.

However, endogenous GLP-1 is rapidly degraded primarily by dipeptidyl peptidase-4 (DPP-4), but also neutral endopeptidase 24.11 (NEP 24.11) and renal clearance, resulting in a half-life of approximately 2 minutes. Consequently, only 10–15 % of GLP-1 reaches circulation intact leading to fasting plasma levels of only 0–15 pmol/L. To overcome this, GLP-1 receptor agonists and DPP-4 inhibitors have been developed to resist and reduce this activity, respectively. As opposed to common treatment agents such as insulin and sulphonylurea, GLP-1-based treatment has been associated with weight loss and lower hypoglycemia risks—two very important aspects of a life with type 2 diabetes.

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