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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments ␤ cell mass via activation of ␤ cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce ␤ cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced ␤ cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased ␤ cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat ␤ cells exposed to interleukin 1␤, tumor necrosis fator ␣, and interferon ␥ in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of ␤-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of ␤ cell mass in vivo.Glucagon-like peptide-1 (GLP-1) 1 is derived from posttranslational processing of proglucagon in enteroendocrine L cells (1) and is secreted from the distal gut after nutrient ingestion (2). The termination of GLP-1 action by the enzyme dipeptidyl peptidase IV occurs within minutes following GLP-1 secretion (3-5), yet GLP-1 exerts several rapid metabolic actions including stimulation and inhibition of insulin and glucagon secretion, respectively (6 -10). GLP-1 action is essential for glucose homeostasis, because GLP-1 receptor blockade with the antagonist exendin (9 -39) increases blood glucose and decreases levels of circulating insulin in human and rodent studies (11)(12)(13)(14).Activation of GLP-1 receptor signaling leads to enhanced expression of mRNA transcripts for glucokinase, GLUT-2, Pdx-1, and insulin in ␤ cell lines (15-17) and in both normal and diabetic rodents (18 -20). Furthermore, GLP-1 and exendin-4 promote differentiation of exocrine cell lines toward a ␤ cell phenotype (21), a process that appears to depend on the expression of Pdx-1 (22, 23).GLP-1 receptor signaling is also coupled to formation of new ␤ cells through enhanced proliferation of existing ␤ cells (24) and via induction of islet neogenesis (25). The mitogenic actions of GLP-1 are detectable in normal rodents (20,24) and in the setting of experimental diabetes (19,25). Administration of GLP-1 or exendin-4 to newborn rats treated with the ␤ cell toxin streptozotocin (STZ) leads to increased ␤ cell mass at postnatal day 7, which persists and remains increased at 2 months of age. The increased ␤ cell mass in the GLP-1/exendin-4 treated rats was attributed to both enhan...

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic β cells, causing impaired insulin secretion. IL-1β is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1β inhibits β cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-κB. Recently, we have shown that increased glucose concentrations also induce Fas expression and β cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1β may mediate the deleterious effects of high glucose on human β cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1β, followed by NF-κB activation, Fas upregulation, DNA fragmentation, and impaired β cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. β cells themselves were identified as the islet cellular source of glucose-induced IL-1β. In vivo, IL-1β–producing β cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1β was induced in β cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented β cell expression of IL-1β. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1β/NF-κB pathway as a target to preserve β cell mass and function in this condition

There is a crucial need for noninvasive assessment tools after cell transplantation. This study investigates whether a magnetic resonance imaging (MRI) strategy could be clinically applied to islet transplantation. The purest fractions of seven human islet preparations were labeled with superparamagnetic iron oxide particles (SPIO, 280 lg/mL) and transplanted into four patients with type 1 diabetes. MRI studies (T2 * ) were performed prior to and at various time points after transplantation. Viability and in vitro and in vivo functions of labeled islets were similar to those of control islets. All patients could stop insulin after transplantation. The first patient had diffuse hypointense images on her baseline liver MRI, typical for spontaneous high iron content, and transplant-related modifications could not be observed. The other three patients had normal intensity on pretransplant images, and iron-loaded islets could be identified after transplantation as hypointense spots within the liver. In one of them, i.v. iron therapy prevented subsequent visualization of the spots because of diffuse hypointense liver background. Altogether, this study demonstrates the feasibility and safety of MRI-based islet graft monitoring in clinical practice. Iron overload (spontaneous or induced) represents the major obstacle to the technique.

Aim The goal of this European Society of Coloproctology (ESCP) guideline project is to give an overview of the existing evidence on the management of diverticular disease, primarily as a guidance to surgeons. Methods The guideline was developed during several working phases including three voting rounds and one consensus meeting. The two project leads (JKS and EA) appointed by the ESCP guideline committee together with one member of the guideline committee (WB) agreed on the methodology, decided on six themes for working groups (WGs) and drafted a list of research questions. Senior WG members, mostly colorectal surgeons within the ESCP, were invited based on publication records and geographical aspects. Other specialties were included in the WGs where relevant. In addition, one trainee or PhD fellow was invited in each WG. All six WGs revised the research questions if necessary, did a literature search, created evidence tables where feasible, and drafted supporting text to each research question and statement. The text and statement proposals from each WG were arranged as one document by the first and last authors before online voting by all authors in two rounds. For the second voting ESCP national representatives were also invited. More than 90% agreement was considered a consensus. The final phrasing of the statements with < 90% agreement was discussed in a consensus meeting at the ESCP annual meeting in Vienna in September 2019. Thereafter, the first and the last author drafted the final text of the guideline and circulated it for final approval and for a third and final online voting of rephrased statements. Results This guideline contains 38 evidence based consensus statements on the management of diverticular disease. Conclusion This international, multidisciplinary guideline provides an up to date summary of the current knowledge of the management of diverticular disease as a guidance for clinicians and patients.