Glucagon-Like peptide-1 (GLP-1) is a 30 or 31 amino acid long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. 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 is susceptible to amidation and proteolytic cleavage which gives rise to the two truncated and equipotent biologically active forms, GLP-1 amide and GLP-1. 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 an incretin thus, it has the 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.

Endogenous GLP-1 is rapidly degraded primarily by Dipeptidyl Peptidase-4 (DPP-4), as well as 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 increase GLP-1 activity. As opposed to common treatment agents such as insulin and sulphonylurea, GLP-1-based treatment has been associated with weight loss and a lower risk of hypoglycemia, two important considerations for patients with type 2 diabetes.

The proglucagon gene is expressed in several organs including the pancreas (α-cells of the islets of Langerhans), gut (intestinal enteroendocrine L-cells) and brain (caudal brainstem and hypothalamus). Pancreatic proglucagon gene expression is promoted upon fasting and hypoglycaemia induction and inhibited by insulin. Conversely, intestinal proglucagon gene expression is reduced during fasting and stimulated upon food consumption. In mammals, the transcription gives rise to identical mRNA in all three cell types, which is further translated to the 180 amino acid precursor called proglucagon. However, as a result of tissue-specific posttranslational processing mechanisms, different peptides are produced in the different cells.

In the pancreas (α-cells of the islets of Langerhans), proglucagon is cleaved by Prohormone Convertase (PC) 2 producing glicentin-related pancreatic peptide, glucagon, intervening peptide-1 and major proglucagon fragment. In the gut and brain, proglucagon is catalysed by PC 1/3 giving rise to glicentin, which may be further processed to GRPP and oxyntomodulin, GLP-1, Intervening Peptide-2 (IP-2) and glucagon-like peptide-2 (GLP-2). Initially, GLP-1 was thought to correspond to proglucagon suitable with the N-terminal of the MGPF, but sequencing experiments of endogenous GLP-1 revealed a structure corresponding to proglucagon from which two discoveries were found. Firstly, the full-length GLP-1 was found to be catalysed by endopeptidase to the biologically active GLP-1.

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Regards,
Morgan E,
Editorial Manager,
Journal of Clinical Diabetes.

E-mail: clindiabetes@eclinicalsci.com