Pancreatic islet transplantation has the potential to be an effective treatment for type 1 diabetes mellitus. While recent improvements have improved 1-year outcomes, follow-up studies show a persistent loss of graft function/survival over 5 years. One possible cause of islet transplant failure is the immunosuppressant regimen required to prevent alloimmune graft rejection. Although there is evidence from separate studies, mostly in rodents and cell lines, that FK506 (tacrolimus), rapamycin (sirolimus), and mycophenolate mofetil (MMF; CellCept) can damage pancreatic beta-cells, there have been few side-by-side, multiparameter comparisons of the effects of these drugs on human islets. In the present study, we show that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets. FK506 had acute and direct effects on insulin exocytosis, whereas MMF did not. FK506, but not MMF, impaired human islet graft function in diabetic NOD*scid mice. All of the immunosuppressants tested in vitro increased caspase-3 cleavage and caspase-3 activity, whereas MMF induced ER-stress to the greatest degree. Treating human islets with the GLP-1 agonist exenatide ameliorated the immunosuppressant-induced defects in glucose-stimulated insulin release. Together, our results demonstrate that immunosuppressants impair human beta-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment.

Islet transplantation yields improved HbA1c and less progression of retinopathy compared with intensive medical therapy during 3 years follow-up.

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Hypothesis: A local multiorgan donor pancreas procurement program can provide a source for optimized isolation of purified viable islets for transplantation into patients with type 1 diabetes mellitus receiving best medical therapy.

The human gastric pathogen Helicobacter pylori attaches to antral epithelial cells in vivo. Cultured human antral epithelial cells, AGS and NCI-N87 cell lines, were grown in the absence or presence of H. pylori and compared with respect to gene transcript levels, protein expression, organization of the actin cytoskeleton, and the regulation of cell migration. The Clontech Neurobiology array detected differentially expressed transcripts, while Western blots were used to investigate related changes in protein levels. Infection with H. pylori consistently upregulated annexin II, S100 A7, Rho-GTP, and IQGAP-1, whereas SSTR-1 was downregulated upon H. pylori infection. In the adherens junction, E-cadherin and IQGAP-1 were translocated from the plasma membrane to intracellular vesicles. The primary and NCI-N87 cells were similar with respect to cell-cell and cell-matrix adhesion and cell migratory behavior; in contrast the AGS cells were significantly different from the primary gastric epithelial cell preparations, and thus caution must be used when using this cell line for studies of gastric disease. These studies demonstrate a correlation between H. pylori infection and alterations to epithelial cell adhesion molecules, including increased levels of Rho-GTP and cell migration. These data indicate that destabilizing epithelial cell adherence is one of the factors increasing the risk of H. pylori-infected individuals developing gastric cancer.Helicobacter pylori is a spiral, gram-negative rod that attaches specifically to the gastric epithelial cells lining the antrum of the stomach (2). H. pylori is able to withstand the hostile environment of the stomach by secretion of urease buffers, which neutralize the pH of its immediate surroundings. Flagella allow these highly motile bacteria to cross the mucous lining of the stomach and to attach to the apical surface of the mucosal epithelial cells. These antral epithelial cells are linked together at the apical surface by a system of interacting proteins that comprise the tight and adherens junctions (12, 31). These junctions effectively seal off the lumen of the stomach, preventing access of gastric acid and pathogens to the interstitial space and, hence, to the general circulation.Individuals infected by H. pylori have increased gastrin levels and decreased levels of somatostatin (SST) hormones that regulate gastric acid secretion. As a result, infected individuals develop mucosal gastritis, increasing their risk of ulceration and, in the longer term, gastric cancer (10, 11). Gastric adenocarcinomas show characteristic changes in the expression of E-cadherin, a transmembrane protein forming the core of the adherens junction. Loss of the E-cadherin complex at the apical pole is thought to induce loss of cell-cell adhesion (34). Direct evidence of E-cadherin mutations triggering tumorigenesis has come from recent studies linking inactivating germ line mutations of the E-cadherin gene (CDH1) in hereditary diffuse gastric cancer (33). Furthermore, it has been shown that the ...