Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance

OBJECTIVES—We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes

Small Interfering RNA–Mediated Suppression of Proislet Amyloid Polypeptide Expression Inhibits Islet Amyloid Formation and Enhances Survival of Human Islets in Culture

OBJECTIVE—Islet amyloid, formed by aggregation of the β-cell peptide islet amyloid polypeptide (IAPP; amylin), is a pathological characteristic of pancreatic islets in type 2 diabetes. Toxic IAPP aggregates likely contribute to the progressive loss of β-cells in this disease. We used cultured human islets as an ex vivo model of amyloid formation to investigate whether suppression of proIAPP expression would inhibit islet amyloid formation and enhance β-cell survival and function

The role of copper(II) in the aggregation of human amylin

Amylin is the 37-residue peptide hormone produced by the islet β-cells in the pancreas and the formation of amylin aggregates is strongly associated with β-cells degeneration in type 2 diabetes, as demonstrated by more than 95% of patients exhibiting amylin amyloid upon autopsy. It is widely recognized that metal ions such as copper(II) have been implicated in the aggregation process of amyloidogenic peptides such as Aβ and α-synuclein and there is evidence that also amylin self-assembly is largely affected by copper(II). For this reason, in this work, the role of copper(II) in the aggregation of amylin has been investigated by several different experimental approaches. Mass spectrometric investigations show that copper(II) induces significant changes in the amylin structure which decrease the protein fibrillogenesis as observed by ThT measurements. Accordingly, solid-state NMR experiments together with computational analysis carried out on a model amylin fragment confirmed the non fibrillogenic nature of the copper(II) induced aggregated structure. Finally, the presence of copper(II) is also shown to have a major influence on amylin proneness to be degraded by proteases and cytotoxicity studies on different cell cultures are reported

Adapting an OHS management system to ISO 45001 requirements : ensuring system management effectiveness

PURPOSE: In the end of a transition period, companies face the need to adjust their existing health and safety management systems to compliance with the ISO 45001 standard. Such compliance is deemed necessary for the effective rollout of a system that will ensure occupational safety. The aim of this study is to adapt the existing solutions for compliance with ISO 45001.DESIGN/METHODOLOGY/APPROACH: The paper relies on the case of two manufacturing companies, for which compliance levels and the nature of any non-compliances have been assessed and for which vital improvement measures have been identified. Issues arising in connection with an assessment of the effectiveness of systemic management are examined. In assessing the solutions in place, the assumption is made that effective improvements are critical for the benefits to be derived from the operation of the resulting OHS system.FINDINGS: A literature review has shown that for occupational safety to be managed effectively, is crucial to resolve all irregularities promptly by means of effective improvement measures. A relevant principle is applied to identify issues and select appropriate improvements. The measures that effectively improve the system in place are instrumental.PRACTICAL IMPLICATIONS: The study addresses the activities that are pivotal for effective occupational safety management and, specifically, for the safety management system to produce the desired effects.ORIGINALITY/VALUE: The study finds which non-conformities prevent organizations from improving their occupational health and safety management systems in accordance with ISO 45001 guidelines. Once organization recognize the needs for improvement that have been identified, they can view their occupational safety management as part of their companywide management system. This has the effect of making their performance more effective.peer-reviewe

Is interleukin-3 important in antiphospholipid anti body-mediated pregnancy failure?

Objective: To investigate the effect of interleuldn-3 (IL-3) on trophoblast proliferation and expression of beta (2)-glycoprotein I

Suppression by polycyclic compounds of the conversion of human amylin into insoluble amyloid.

There is a significant correlation between the occurrence of pancreatic islet amyloid and beta-cell failure in advanced type II diabetes mellitus. Islet amyloid is composed primarily of the fibrillar form of the pancreatic hormone, amylin. Using thioflavin-T fluorescence binding and radioprecipitation assays, we investigated whether or not a series of small tricyclic compounds, tetracycline or Congo Red could interfere with the conversion of synthetic human amylin into its insoluble amyloid form. Of the compounds investigated, incubation of human amylin with a 20-fold molar excess of either Congo Red or Acridine Orange resulted in significant inhibition in the rate of amyloid formation. With Congo Red, maximal inhibition effectively occurred at a 1:1 molar ratio or greater over human amylin, whereas inhibition by Acridine Orange was dose-dependent. A 20-fold molar excess of the compound tetracycline also decreased insoluble amyloid content after extended incubation periods of approx. 20 h. Amyloid fibril morphology in the presence of tetracycline, as measured by transmission electron microscopy, was characterized by short fragmented fibrils compared with the longer and denser appearance of fibrils formed by amylin alone. These findings show that polycyclic compounds can suppress the formation of amyloid by human amylin, providing support for an alternative approach to peptide-based strategies by which islet amyloid formation could be modulated

Copper-mediated formation of hydrogen peroxide from the amylin peptide:a novel mechanism for degeneration of islet cells in type-2 diabetes mellitus?

Amyloid deposits derived from the amylin peptide accumulate within pancreatic islet P-cells in most cases of type-2 diabetes mellitus (T2Dm). Human amylin 'oligomers' are toxic to these cells. Using two different experimental techniques, we found that H2O2 was generated during the aggregation of human amylin into amyloid fibrils. This process was greatly stimulated by Cu(II) ions, and human amylin was retained on a copper affinity column. In contrast, rodent amylin, which is not toxic, failed to generate any H2O2 and did not interact with copper. We conclude that the formation Of H202 from amylin could contribute to the progressive degeneration of islet cells in T213m. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved