This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes mellitus and impaired glucose tolerance (IGT) are the most common co-morbidities among persons with cystic fibrosis (CF). Despite considerable research into the reasons in cystic fibrosis, its exact mechanism remains elusive. Beta cell destruction leading to insulin depletion, along with underlying insulin resistance from chronic illness are believed to be the major causes of cystic fibrosis related diabetes (CFRD). However, all CF patients with pancreatic insufficiency develop abnormal pancreatic histology; but only some develop IGT or diabetes. The IGT or diabetes in cystic fibrosis is also unique in that normal fasting with abnormal post-prandial blood sugars are commonly seen. This phenomenon is rarely seen in type 1 diabetes. Glucagon-like peptide-1 (GLP-1) is an intestinally derived incretin polypeptide hormone that mediates insulin secretion, insulin gene expression, beta-cell growth and differentiation, and helps regulate plasma glucose levels (1, 2, 4). In addition, GLP-1 inhibits glucagon secretion, inhibits gastric emptying and reduces appetite and food intake (2). GLP-1 is produced through the posttranslational processing of proglucagon from the enteroendocrine L cells in the intestinal mucosa (1). GLP-1 is secreted in response to meal ingestion and along with D-glucose, acts on GLP-1 receptors in pancreatic beta-cells to stimulate insulin secretion. Studies have demonstrated that interference with the incretin function of GLP-1 causes glucose intolerance (3). In patients with type 2 diabetes, the release of intestinal GLP-1 from oral glucose stimulation is decreased compared to healthy normal glucose tolerant controls (3). In type 1 diabetes patients, there is no increase in postprandial GLP-1 levels despite normal basal peptide secretion. In either insulin resistance or insulin deficiency, the chronic hyperglycemia causes progressive desensitization of intestinal L-cells which contributes to the subsequent failure of GLP-1 secretion to food ingestion (4). A single gene in mammals produces an identical proglucagon RNA transcript that is translated and processed differently in pancreatic islet cells and the intestine, giving rise to glucagon and GLP-1, respectively (1). The release of GLP-1 in the intestine, but not in the pancreas, is due to tissue-specific expression of prohoromone convertases in the enteroendocrine cells of the small intestine (1). GLP-1 exerts its action on GLP-1 receptors by binding to a G-protein-linked receptor whose signaling is coupled to both the activation of adenylate cyclase and phospholipase C pathways (1). These receptors have been found on islet beta-cells of the pancreas, as well as tissues of the lung, kidney, stomach, heart, and brain (1). Therefore, any disruption either at the level of GLP-1 production or release from the intestinal cells, or at the target organ such as the insulin producing islet cells could cause an abnormal response to glucose ingestion. In cystic fibrosis, both pancreatic ductal cells and gut epithelial cells are affected through the mutation of the CFTR gene. The CFTR gene is normally expressed in epithelial cells on the pancreatic exocrine ducts and the epithelial cells lining the gastrointestinal tract. An abnormally functioning gut epithelial cell may theoretically affect the expression of proglucagon, the post-translational processing of GLP-1, the release of GLP-1, or a combination of these. Additionally, the reduction in pancreatic mass that is common among people with cystic fibrosis may be due to reduction in GLP-1 or in the GLP-1 receptor, rendering the islet cells unresponsive or resistant to GLP-1. Either of these phenomena could explain the unique and common feature of glucose intolerance seen in people with cystic fibrosis.
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