ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 P53

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

NM James1, LE Pritchard1, JC Brennand2 & A White1

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.

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