2006 Abstracts

 

A clinical screening tool identifies autoimmune diabetes in adults

Fourlanos S, Perry C, Stein MS, Stankovich J, Harrison LC, Colman PG

Diabetes Care. 29:970-975 (2006)

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS: Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA-) (aged 30-75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a "LADA clinical risk score," based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS: In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset <50 years (P < 0.0001), 2) acute symptoms (P < 0.0001), 3) BMI <25 kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score > or =2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score < or =1 of 99%. CONCLUSIONS: At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.

[View free full-text article on Diabetes Care website]

 

TCR gamma delta intraepithelial lymphocytes are required for self-tolerance

Locke NR, Stankovic S, Funda DP, Harrison LC

J Immunol 176:6553-6559 (2006)

Neonatal thymectomy (NTX) impairs T cell regulation and leads to organ-specific autoimmune disease in susceptible mouse strains. In the NOD mouse model of spontaneous type 1 diabetes, we observed that NTX dramatically accelerated autoimmune pancreatic beta cell destruction and diabetes. NTX had only a minor effect in NOD mice protected from diabetes by transgenic expression of the beta cell autoantigen proinsulin in APCs, inferring that accelerated diabetes after NTX is largely due to failure to regulate proinsulin-specific T cells. NTX markedly impaired the development of intraepithelial lymphocytes (IEL), the number of which was already reduced in euthymic NOD mice compared with control strains. IEL purified from euthymic NOD mice, specifically CD8alphaalpha TCRgammadelta IEL, when transferred into NTX-NOD mice, trafficked to the small intestinal epithelium and prevented diabetes. Transfer of prototypic CD4+CD25+ regulatory T cells also prevented diabetes in NTX-NOD mice; however, the induction of these cells by oral insulin in euthymic mice depended on the integrity of TCRgammadelta IEL. We conclude that TCRgammadelta IEL at the mucosal interface between self and nonself play a key role in maintaining peripheral tolerance both physiologically and during oral tolerance induction.

[View free full-text article on J Immunol website]

 

Proinsulin is encoded by an RNA splice variant in human blood myeloid cells

Narendran P, Neale AM, Lee BH, Ngui K, Steptoe RJ, Morahan G, Madsen O, Dromey JA, Jensen KP, Harrison LC

Proc Natl Acad Sci U S A 103:16430-16435 (2006)

Genes for peripheral tissue-restricted self-antigens are expressed in thymic and hematopoietic cells. In thymic medullary epithelial cells, self-antigen expression imposes selection on developing autoreactive T cells and regulates susceptibility to autoimmune disease in mouse models. Less is known about the role of self-antigen expression by hematopoietic cells. Here we demonstrate that one of the endocrine self-antigens expressed by human blood myeloid cells, proinsulin, is encoded by an RNA splice variant. The surface expression of immunoreactive proinsulin was significantly decreased after transfection of monocytes with small interfering RNA to proinsulin. Furthermore, analogous to proinsulin transcripts in the thymus, the abundance of the proinsulin RNA splice variant in blood cells corresponded with the length of the variable number of tandem repeats 5' of the proinsulin gene, known to be associated with type 1 diabetes susceptibility. Self-antigen expression by peripheral myeloid cells extends the umbrella of "immunological self" and, by analogy with the thymus, may be implicated in peripheral immune tolerance.

[View free full-text article on Proc Natl Acad Sci U S A website]

 

Retrospective data for diabetic foot complications: only the tip of the iceberg?

Wraight PR, Lawrence SM, Campbell DA, Colman PG

Intern Med J 36:197-199 (2006)

Admission rates for diabetes-related foot complications to an Australian hospital were assessed by comparing the frequently used method of retrospectively identifying patients according to International Classification of Diseases (ICD) codes with that of prospectively identifying patients at the time of admission. The aim was to determine the true admission rate of diabetes-related foot complications and to assess the ability of ICD discharge codes to accurately represent the clinical severity of each identified admission. The retrospective study of ICD codes identified approximately one-third of the patients admitted during the prospective studies. Furthermore, ICD codes allocated in the prospective studies failed to accurately represent the clinical condition in 61% of cases and the corresponding Weighted Inlier Equivalent Separations weighting resulted in a $215,000/year deficit for admissions to a single hospital.

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