1Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3 untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans. Diabetes 51: [2012][2013][2014][2015][2016][2017] 2002 R ecent data from knock-out mice (1) and in vitro studies (2-5) have identified type II SH2-domain-containing inositol 5-phosphatase, or "SHIP2," as a critical and essential negative regulator of insulin signaling and sensitivity. Indeed, decreased expression of SHIP2 and SHIP2 deficiency in mice leads to increased insulin sensitivity, whereas SHIP2 overexpression in various insulin-sensitive cell lines leads to decreased insulin signaling, i.e., insulin resistance. Given the importance of SHIP2 in the control of insulin sensitivity, we postulated that mutation(s) positively affecting SHIP2 activity, function, and/or expression might contribute to insulin resistance, a hallmark of type 2 diabetes. RESEARCH DESIGN AND METHODSLocalization of the SHIP2 gene on rat chromosomes. Fluorescent in situ hybridization and radiation hybrids mapping were performed as described (6). The following forward and reverse primers were used to amplify a 140-bp DNA fragment of the rat SHIP2 gene from hybrid DNA: 5Ј-CCAGGGGT GAAAGTTTTGAG-3Ј and 5Ј-CCTGACCCTGGGCCTAAAAG-3Ј. SHIP2 gene amplification and sequencing in humans and rats. Consent was obtained from all subjects after the nature of the procedure was explained, and the investigation was conducted according to the principles expressed in the Declaration of Helsinki. All diabetic subjects were Ͼ35 years of age at diagnosis and met the World Health Organization's criteria defining diabetes status. The control subjects were randomly and anonymously chosen in a DNA library isolated from a large population of women consulting for a genetic diagnosis of mutation in the CFTR gene. The SHIP2 cDNA and gene sequences were obtained after PCR amplification. The sequencing products were run on an Applied Biosystem sequencer. CHO-IR transfection, Akt/protein kinase B, and mitogen-activated protein kinase activities. CHO cells expressing...

The EQAS results presented in this work provide valuable insights into the state of the art of ANA testing as practiced in the Belgian and Luxembourg Laboratories and illustrate the important value of a national EQAS for ANA testing as a tool to improve performance and interlaboratory comparability of laboratory results.

Autoantibodies to nuclear antigens, i.e. antinuclear antibodies (ANA), antibodies to double-stranded DNA (dsDNA) and extractable nuclear antigens (ENA), are useful as diagnostic markers for a variety of autoimmune diseases. In March 2010, the Belgian national External Quality Assessment Scheme sent a questionnaire on ANA, anti-dsDNA and anti-ENA antibody testing designed by the Dutch EASI (European Autoimmunity Standardization Initiative) team, to all clinical laboratories performing ANA testing. Virtually all laboratories completed the questionnaire (97·7%, 127/130). This paper discusses the results of this questionnaire and provides valuable information on the state-of-the-art of ANA, anti-dsDNA and anti-ENA antibody testing as practiced in the Belgian laboratories. In addition, this work presents practical recommendations developed by the members of the advisory board of the scheme as a result of the outcome of this study.

Objective-Autoantibodies to cell membrane associated DNA are described in systemic lupus erythematosus (SLE). The specificity of these antibodies diVer from antibodies to nuclear DNA. Methods-Using

Over a 2-year period, thyroid function was studied in 102 patients infected with the human immunodeficiency virus (HIV) and in 102 age- and sex-matched controls with various infectious diseases. Biochemical abnormalities were observed in 1-20% of the patients, depending on thyroid indices, but thyroid disease (hypothyroidism) was diagnosed in only 1. Compared to controls, patients, especially those with the acquired immunodeficiency syndrome (AIDS), had a significant increase in serum thyroxine-binding globulin, a lower T3 and free thyroxine index, and a higher frequency of thyroglobulin antibodies.