Kynurenine-3-monooxygenase expression is activated in the pancreatic endocrine cells by diabetes and its blockade improves glucose-stimulated insulin secretion.

Type 2 diabetes is associated with an inflammatory phenotype in the pancreatic islets. We previously demonstrated that proinflammatory cytokines potently activate the tryptophan/kynurenine pathway (TKP) in INS-1 cells and in normal rat islets. Here we examined: (1) the TKP enzymes expression in the diabetic GK islets; (2) the TKP enzymes expression profiles in the GK islets before and after the onset of diabetes; (3) The glucose-stimulated insulin secretion (GSIS) in vitro in GK islets after KMO knockdown using specific morpholino-oligonucleotides against KMO or KMO blockade using the specific inhibitor Ro618048; (4) The glucose tolerance and GSIS after acute in vivo exposure to Ro618048 in GK rats.

Proprotein convertase PCSK9 affects expression of key surface proteins in human pancreatic beta cells via intracellular and extracellular regulatory circuits.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the degradation of the low-density lipoprotein receptor. PCSK9 also targets proteins involved in lipid metabolism (very low-density lipoprotein receptor), immunity (major histocompatibility complex I), and viral infection (cluster of differentiation 81). Recent studies have also indicated that PCSK9 loss-of-function mutations are associated with an increased incidence of diabetes; however, the expression and function of PCSK9 in insulin-producing pancreatic beta cells remain unclear.

Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3.

Glucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood.

Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function.

Background And Aims: Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) is an endogenous inhibitor of the LDL receptor (LDLR). Mendelian randomization studies suggest that PCSK9 deficiency increases diabetes risk, but the underlying mechanisms remain unknown. The aim of our study was to investigate whether PCSK9 or its inhibition may modulate beta cell function.

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells.

Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice.

Regulated expression and function of the GABA receptor in human pancreatic beta cell line and islets.

G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. They constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases.

Correction to: Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features.

An amendment to this paper has been published and can be accessed via the original article.

Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features.

Background: Mesenchymal stromal cells (MSCs) represent an interesting tool to improve pancreatic islet transplantation. They have immunomodulatory properties and secrete supportive proteins. However, the functional properties of MSCs vary according to many factors such as donor characteristics, tissue origin, or isolation methods.

The flanking peptides issue from the maturation of the human islet amyloid polypeptide (hIAPP) slightly modulate hIAPP-fibril formation but not hIAPP-induced cell death.

Type 2 diabetes mellitus is a disease characterized by the formation of amyloid fibrillar deposits consisting mainly in human islet amyloid polypeptide (hIAPP), a peptide co-produced and co-secreted with insulin. hIAPP and insulin are synthesized by pancreatic β cells initially as prehormones resulting after sequential cleavages in the mature peptides as well as the two flanking peptides (N- and C-terminal) and the C-peptide, respectively. It has been suggested that in the secretory granules, the kinetics of hIAPP fibril formation could be modulated by some internal factors.

Implication of glycogen synthase kinase 3 in diabetes-associated islet inflammation.

Islet inflammation is associated with defective β cell function and mass in type 2 diabetes (T2D). Glycogen synthase kinase 3 (GSK3) has been identified as an important regulator of inflammation in different diseased conditions. However, the role of GSK3 in islet inflammation in the context of diabetes remains unexplored.

Conventional and Neo-antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors.

Although CD8 T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression.

MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells.

Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes.

Extracellular acidification stimulates GPR68 mediated IL-8 production in human pancreatic β cells.

Acute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic β-cell dysfunction. However, the mechanisms by which human β-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human β-cell line EndoC-βH2, we demonstrate that β-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human β-cells.

Cell rearrangement in transplanted human islets.

The major feature of the human pancreatic islet architecture is the organization of endocrine cells into clusters comprising central β cells and peripheral α cells surrounded by vasculature. To have an insight into the mechanisms that govern this unique islet architecture, islet cells were isolated, and reaggregation of α and β cells into islet-like structures (pseudoislets) after culture or transplantation into mice was studied by immunohistology. The pseudoislets formed in culture displayed an unusual cell arrangement, contrasting with the transplanted pseudoislets, which exhibited a cell arrangement similar to that observed in native pancreatic islet subunits.

A proprietary blend of quail egg for the attenuation of nasal provocation with a standardized allergenic challenge: a randomized, double-blind, placebo-controlled study.

Occasional rhinitis symptoms caused by exposure to pollution or allergens is a growing concern. Based first on empirical observation of a lesser occurrence of allergies in quail farmers and then scientific works on ovomucoids properties, we developed a dietary supplement for the relief of such occasional rhinitis symptoms. The objective of the study was to determine whether one acute oral dose of the study product attenuates nasal provocation and other allergy-related symptoms after exposure to a standardized allergenic challenge as compared to placebo.

Correction: proteasome dysfunction mediates high glucose-induced apoptosis in rodent Beta cells and human islets.

[This corrects the article DOI: 10.1371/journal.pone.

Proteasome dysfunction mediates high glucose-induced apoptosis in rodent beta cells and human islets.

The ubiquitin/proteasome system (UPS), a major cellular protein degradation machinery, plays key roles in the regulation of many cell functions. Glucotoxicity mediated by chronic hyperglycaemia is detrimental to the function and survival of pancreatic beta cells. The aim of our study was to determine whether proteasome dysfunction could be involved in beta cell apoptosis in glucotoxic conditions, and to evaluate whether such a dysfunction might be pharmacologically corrected.

[Evaluation of the management of COPD exacerbations: an audit in French emergency services].

Introduction: Acute exacerbations of chronic obstructive pulmonary disease (COPD) patients are major events in the history of this chronic respiratory disease. Their management in French emergency services is unknown, although national guidelines exist.

Methods: This is a descriptive audit study, over a 10 weeks period (12/01-22/03/2009), of the management of COPD exacerbations in the RESUVal (Réseau des Urgences de la Vallée du Rhône, France) network emergency departments.

Fetal PGC-1α overexpression programs adult pancreatic β-cell dysfunction.

Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation.

A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion.

Despite intense efforts over the past 30 years, human pancreatic β cell lines have not been available. Here, we describe a robust technology for producing a functional human β cell line using targeted oncogenesis in human fetal tissue. Human fetal pancreatic buds were transduced with a lentiviral vector that expressed SV40LT under the control of the insulin promoter.

Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice.

Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear.

A novel method for quantitative monitoring of transplanted islets of langerhans by positive contrast magnetic resonance imaging.

The Automatic Quantitative Ultrashort Echo Time imaging (AQUTE) protocol for serial MRI allows quantitative in vivo monitoring of iron labeled pancreatic islets of Langerhans transplanted into the liver, quantifying graft implantation and persistence in a rodent model. Rats (n = 14), transplanted with iron oxide loaded cells (0-4000 islet equivalents, IEQ), were imaged using a 3D radial ultrashort echo time difference technique (dUTE) on a Siemens MAGNETOM 3T clinical scanner up to 5 months postsurgery. In vivo 3D dUTE images gave positive contrast from labeled cells, suppressing liver signal and small vessels, allowing automatic quantification.

Combined pancreatic islets-lung transplantation in cystic fibrosis-related diabetes: case reports.

Unlabelled: We report two cases of percutaneous portal embolization of pancreatic islets performed after double lung transplantation in cystic fibrosis (CF) patients using the pancreas of the same donor. CASE 1: A 19-year-old man with CF had insulin-dependent diabetes, which was poorly controlled despite an external insulin pump (96 IU/d): HbA(1c) = 9.8% and 1 to 3 hypoglycemic events per day.