Role of the Prohormone Convertase PC3 in the Processing of Proglucagon to Glucagon-like Peptide 1

Rouillé, Yves; Kantengwa, Salomé; Irminger, Jean-Claude; Halban, Philippe A.

doi:10.1074/jbc.272.52.32810

Cited by 95 publications

(52 citation statements)

References 67 publications

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“…Interestingly, the NH 2 -terminal cleavage site of GLP-1 is not a classical pair of basic amino acids, but represents a single Arg residue; however, in vitro coexpression of PC 1/3 and proglucagon has demonstrated efficient cleavage at this site (255). In agreement with this, mutations in PC 1/3 lead to abnormalities in GLP-1 processing and secretion, associated with multiple endocrinopathies (143) (undoubtedly because PC 1/3 is important for processing of many regulatory peptides/hormones), and mice with a targeted deletion of the PC-1/3 gene are unable to process proglucagon to GLP-2 and GLP-1 (295,344).…”

Section: Proglucagon Gene Expression Posttranslational Processinmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,650

2,385

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Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

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Section: Proglucagon Gene Expression Posttranslational Processinmentioning

confidence: 99%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,650

2,385

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“…The presence of different processing enzymes allows cell-specific products to be generated from the same precursor. In the L-cells, prohormone convertase (PC)1/3 is responsible for the generation of GLP-1 and GLP-2, whereas the alpha cells produce glucagon as a result of processing by PC 2, leaving the active form of the GLP-1 peptide trapped in a larger fragment, the major proglucagon fragment [8,9]. After GLP-1 is released from the intestinal L-cells to the circulation, it is very rapidly degraded to an inactive metabolite (GLP-1 ) by the enzyme dipeptidyl peptidase 4 (DPP-IV) and only a small fraction reaches the pancreatic beta cells that express the GLP-1 receptor [10,11] The prevailing view is that in adults, all circulating GLP-1 is produced by the intestinal L-cells, with no contribution from the alpha cells as they are thought not to produce PC1/3, thus excluding GLP-1 production.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus—an adaptive response to hyperglycaemia?

et al. 2011

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“…In the islets of Langerhans, proglucagon is synthesized in the A-cells and processed to glucagon, GRPP, IP-1, and major proglucagon fragment (MPGF), which contains the unprocessed GLP-1, IP-2, and GLP-2 sequences (12,13,16). Only very low levels of GLP-1 are generated in the A-cells, whereas GLP-1 and -2 are major products of proglucagon processing in L-cells, along with glicentin, the intact N-terminal domain that contains unprocessed glucagon (17)(18)(19).…”

mentioning

confidence: 99%

Severe Defect in Proglucagon Processing in Islet A-cells of Prohormone Convertase 2 Null Mice

Furuta

Zhou

Webb

et al. 2001

Journal of Biological Chemistry

153

117

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. In this report we have examined the biosynthesis and processing of proglucagon in isolated islets from these mice via pulse-chase labeling and find that proglucagon undergoes essentially no processing in chase periods up to 8 h in duration. Only a small percent of cleavage at the sensitive interdomain site (residues 71 and 72) appears to occur. These observations thus conclusively demonstrate the essentiality of PC2 for the production of glucagon in the islet A-cells. Ultrastructural and immunocytochemical studies indicate the presence of large amounts of proglucagon in atypical appearing secretory granules in the hyperplastic and hypertrophic A-cells, along with morphological evidence of high rates of proglucagon secretion in PC2 null islets. These findings provide strong evidence that active glucagon is required to maintain normal blood glucose levels, counterbalancing the action of insulin at all times.

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Role of the Prohormone Convertase PC3 in the Processing of Proglucagon to Glucagon-like Peptide 1

Cited by 95 publications

References 67 publications

The Physiology of Glucagon-like Peptide 1

The Physiology of Glucagon-like Peptide 1

Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus—an adaptive response to hyperglycaemia?

Severe Defect in Proglucagon Processing in Islet A-cells of Prohormone Convertase 2 Null Mice

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