Expression of the glucagon like peptide-1 receptor in human pancreas and incretin therapy.

Incretins are hormones released by gut enteroendocrine cells in response to nutrient ingestion that regulate circulating glucose levels. One member of the incretin family is the glucagon-like peptide-1 (GLP-1), which is secreted by intestinal L cells located mainly in the mucosa of ileum and colon. It is produced by posttranslational processing of the glucagon gene product. GLP-1 binds to a specific receptor (GLP-1R), a seven-transmembrane G proteincoupled receptor originally identified in islet -cells (1) with a broad range of tissue-specific functions (1–8). The binding of GLP-1 to the GLP-1R on pancreatic -cells augments glucose-stimulated insulin secretion, increases transcription of the insulin gene, and enhances both the stability of insulin mRNA and biosynthesis of insulin (reviewed in References 9 and 10). In addition to the glucoregulatory effects, GLP-1 has been reported to protect -cells from apoptosis (11) and to stimulate their neogenesis and proliferation (12, 13). After secretion, GLP-1 is rapidly degraded into GLP-1 (9–36) by the enzyme dipeptidyl-peptidase IV (DPP-4) (14). As a result, the biological half-life of GLP-1 is less than 5 minutes (15). DPP-4 enzymatic activity can be inhibited by DPP-4 inhibitors (DPP-4-i), which prevents the cleavage of GLP-1 and other DPP-4 targets. In doing so, the inhibitor maintains the intact levels of the molecules, improving glucose tolerance (reviewed in Reference 16). Because of their beneficial effect in controlling blood glucose levels, DPP-4is and GLP-1 agonists are current therapies for type 2 diabetes. Recently, however, the use of GLP-1-based therapies has been deemed dangerous by a publication indicating that they increase the risk of pancreatic cancer (17). Similarly, it was also suggested that incretin administration might be related to the development of thyroid cancer (18). One of the leading arguments that underpinned the proposed relationshipbetween incretins andcancersof the pancreas and thyroid was the reported localization of the GLP-1R to the pancreatic duct and acinar tissue (19) of rodents and to the human thyroid gland (18). The hypothesis raised by the authors of those studies proposed that long-term stimulation of cells expressing the GLP-1R resulted in cell hyperplasia and tumor formation. In the human thyroid, neoplastic and hyperplastic lesions of thyroid C cells were reported to contain GLP-1Rimmunopositive cells (18). The experiments analyzing the effect of GLP-1 stimulation in the pancreas were performed in rats receiving daily injections of the GLP-1 analog exendin-4 and in a mouse model of pancreatic cancer. These studies revealed the presence of immune-positive GLP-1R cells in lesions of the pancreatic duct [termed pancreatic duct glands (PDGs)] that appear during chronic injury and in pancreatic intraepithelial neoplasia (PanIN) (19). Because PDGs and PanIN were also found in the pancreas of diabetic patients who received DPP-4is, the conclusion was reached that the inhibitors caused tumor development (17). This report, suggesting a deleterious effect of DPP-4is in the pancreas of human diabetic patient, was highly controversial, mainly because the diabetic groups receiving either incretin therapy or other insulin secretagogues were not comparable with regard to age and duration of the disease. Several publications have already raised severe concerns regarding the clinical aspects of this publication (16, 20–23). A critical issue in the studies reporting a correlation between incretin therapy and cancer development is the