Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 12 P53

SFE2006 Poster Presentations Diabetes, metabolism and cardiovascular (19 abstracts)

Proglucagon processing can be altered to produce GLP-1 in pancreatic alpha cells

NM James 1 , LE Pritchard 1 , JC Brennand 2 & A White 1


1Manchester University, Manchester, United Kingdom; 2AstraZeneca, Macclesfield, Cheshire, United Kingdom.


The proglucagon-derived hormone, glucagon-like peptide–1 (GLP-1), augments both beta cell function and mass. However, GLP-1 is rapidly degraded in plasma, thereby limiting its potential as a treatment for diabetes. One approach to circumvent this problem would be to stimulate synthesis of GLP-1 locally in the islet.

Emerging evidence suggests that pancreatic alpha cells, which normally produce glucagon, can adapt to produce GLP-1. This phenomenon may be related to decreased expression of proprotein convertase-2 (PC-2), the enzyme responsible for glucagon synthesis, because PC2 deficient alpha-cell lines produce GLP-1. To test this hypothesis ex vivo, we have isolated islets from PC2 null (PC2−/−), heterozygous (PC2+/−) and wild-type (PC+/+) mice and have quantified GLP-1 and glucagon in islet lysates, using specific ELISAs. Glucagon levels were decreased in PC2−/− (20.4±1.7 fmol/islet) versus PC2+/+(453.3±43.0 fmol/islet; P<0.05) islets. Conversely GLP-1 levels were increased in PC2−/− (4.7±0.3 fmol/islet) versus PC2+/+(0.3±0.1 fmol/islet; P<0.001) islets. These data indicate that absence of PC2 stimulates GLP-1 synthesis in the islet whilst simultaneously reducing glucagon synthesis.

In parallel, we have tested whether glucotoxicity results in increased PC1 expression, the enzyme responsible for GLP-1 synthesis, by chronically exposing islets to increasing concentrations of glucose (5, 11, and 25 mM). Interestingly, islet PC1 expression was significantly increased after 3 and 7days in 11 and 25 mM glucose, but not after 24 hours. Moreover GLP-1 levels in islet lysates were significantly increased in 7 day cultures (4.1±0.3 fmol/islet) versus 24 hour cultures (2.2±0.2 fmol/islet; P=0.002). Together, these experiments indicate that proglucagon processing in the islet may be adaptable to generate GLP-1, which could have a beneficial paracrine effect on beta cell regeneration.

Volume 12

197th Meeting of the Society for Endocrinology

Society for Endocrinology 

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