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Review
. 2016 Feb 1;16(1):1-7.
doi: 10.17305/bjbms.2015.794.

Do glucagonomas always produce glucagon?

Affiliations
Review

Do glucagonomas always produce glucagon?

Nicolai Jacob Wewer Albrechtsen et al. Bosn J Basic Med Sci. .

Abstract

Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.

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Figures

FIGURE 1
FIGURE 1
Tissue specific processing of proglucagon. In the pancreatic α-cell, proglucagon is processed by PC2 activity into GRPP, glucagon, major proglucagon fragment (MPGF). In the L-cells, proglucagon is processed by PC1/3 into GLP-1 (7-36NH2) GLP-2 and glicentin. By further PC1/3 activity, glicentin can then be further cleaved into glicentin related pancreatic polypeptide (GRPP) and oxyntomodulin. N-terminal elongated glucagon has also been reported and is termed intestinal glucagon or enteroglucagon. Black arrowheads refer to side-viewing proglucagon antibodies, red arrowheads refer to N-terminal glucagon/oxyntomodulin antibodies and blue arrowheads refer to C-terminal glucagon antibodies. Glucagon measurement should therefore be carried out using, preferably a sandwich ELISA employing N and C-terminal glucagon antibodies. Assay only using black, blue or red antibodies (as depicted here) may over or underestimate glucagon levels due to cross-reactivity with other proglucagon molecules such as glicentin, oxyntomodulin or enteroglucagon 1-61.
FIGURE 2
FIGURE 2
The molecular heterogeneity of glucagonomas results in differential clinical phenotype. As illustrated patients suffering with glucagonomas shares common features (right panel) however and clinical important they may depending on the molecular processing of proglucagon also.

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