Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility.

Elevation in interleukin 13 levels in patients diagnosed with systemic inflammatory response syndrome.

Objective: To examine plasma levels and circadian rhythm of interleukin 13 (IL-13), tumour necrosis factor (TNF) alpha and total serum cortisol in the systemic inflammatory response syndrome (SIRS).

Design And Setting: Prospective observational study in a 12-bed medical-surgical ICU of a 500-bed university hospital.

Patients: Ten patients with SIRS and eight controls.

Elevated lymphocyte expression of CLIP is associated with type 1 diabetes and may be a useful marker of autoimmune susceptibility.

Type 1 diabetes (T1D) susceptibility in humans and in the non-obese diabetic mouse is linked to MHC class II molecules characterized by an amino acid substitution at position 57 of the beta-chain (nonAspB57). The mechanism whereby nonAspB57 MHC molecules contribute to diabetes susceptibility is not currently known. As CLIP is displaced from MHC class II molecules upon peptide binding, if nonAspB57 haplotypes are associated with high CLIP expression, this may reflect a defect in peptide loading.

Identification of "pathologs" (disease-related genes) from the RIKEN mouse cDNA dataset using human curation plus FACTS, a new biological information extraction system.

Background: A major goal in the post-genomic era is to identify and characterise disease susceptibility genes and to apply this knowledge to disease prevention and treatment. Rodents and humans have remarkably similar genomes and share closely related biochemical, physiological and pathological pathways. In this work we utilised the latest information on the mouse transcriptome as revealed by the RIKEN FANTOM2 project to identify novel human disease-related candidate genes.

Autoimmune diabetes in the NOD mouse: an essential role of Fas-FasL signaling in beta cell apoptosis.

Despite evidence that both Fas and FasL can be expressed in pancreatic islets, there has been considerable controversy regarding the potential role of Fas signaling in autoimmune beta cell death. Using the HIPFasL model, we have been able to demonstrate that, in the presence of an inflammatory infiltrate, FasL-expressing beta cells are exquisitely sensitive to Fas-mediated apoptosis and that this can be blocked by preventing FasL-Fas interaction. This points to a highly important role of Fas-FasL interaction in autoimmune beta cell death.

Inferring higher functional information for RIKEN mouse full-length cDNA clones with FACTS.

FACTS (Functional Association/Annotation of cDNA Clones from Text/Sequence Sources) is a semiautomated knowledge discovery and annotation system that integrates molecular function information derived from sequence analysis results (sequence inferred) with functional information extracted from text. Text-inferred information was extracted from keyword-based retrievals of MEDLINE abstracts and by matching of gene or protein names to OMIM, BIND, and DIP database entries. Using FACTS, we found that 47.

Mechanisms of accelerated immune-mediated diabetes resulting from islet beta cell expression of a Fas ligand transgene.

Nonobese diabetic (NOD) mice transgenic for Fas ligand (FasL) on islet beta cells (HIPFasL mice) exhibit an accelerated diabetes distinct from the normal autoimmune diabetes of NOD mice. This study was undertaken to define the mechanism underlying accelerated diabetes development in HIPFasL mice. It was found that diabetes in HIPFasL mice is dependent on the NOD genetic background, as HIPFasL does not cause diabetes when crossed into other mice strains and is lymphocyte dependent, as it does not develop in HIPFasL(SCID) mice.

Macrophage migration inhibitory factor exhibits a pronounced circadian rhythm relevant to its role as a glucocorticoid counter-regulator.

In humans, maximal expression of T helper 1 cytokines coincide with the nocturnal nadir of plasma cortisol, whereas T helper 2 cytokine responses are dominant during day-time. The pro-inflammatory cytokine, macrophage migration inhibitory factor counter-regulates glucocorticoid-mediated immune suppression. To determine the relationship between cortisol and macrophage migration inhibitory factor, healthy volunteers had blood drawn hourly for 24 h for measurement of plasma cortisol and basal- and stimulated-macrophage migration inhibitory factor.