Original Data

Type 1 Diabetes Development Requires Both CD4+ and CD8+ T cells and Can Be Reversed by Non-Depleting Antibodies Targeting Both T Cell Populations

Jenny M. Phillips, Nicole M. Parish, Tim Raine, Chris Bland, Yvonne Sawyer, Hugo De La Peña, Anne Cooke

Abstract

Type 1 diabetes development in NOD mice appears to require both CD4⁺ and CD8⁺ T cells. However, there are some situations where it has been suggested that either CD4⁺ or CD8⁺ T cells are able to mediate diabetes in the absence of the other population. In the case of transgenic mice, this may reflect the numbers of antigen-specific T cells able to access the pancreas and recruit other cell types such as macrophages leading to a release of high concentrations of damaging cytokines. Previous studies examining the requirement for CD8⁺ T cells have used antibodies specific for CD8α. It is known that CD8α is expressed not only on αβ T cells, but also on other cell types, including a DC population that may be critical for presenting islet antigen in the pancreatic draining lymph nodes. Therefore, we have re-examined the need for both CD4⁺ and CD8⁺ T cell populations in diabetes development in NOD mice using an antibody to CD8β. Our studies indicate that by using highly purified populations of T cells and antibodies specific for CD8⁺ T cells, there is indeed a need for both cell types. In accordance with some other reports, we found that CD4⁺ T cells appeared to be able to access the pancreas more readily than CD8⁺ T cells. Despite the ability of CD4⁺ T cells to recruit CD11b class II positive cells, diabetes did not develop in the absence of CD8⁺ T cells. These studies support the observation that CD8⁺ T cells may be final effector cells. As both T cell populations are clearly implicated in diabetes development, we have used a combination of non-depleting antibodies to target both CD4-positive and CD8-positive cells and found that this antibody combination was able to reverse diabetes onset in NOD mice as effectively as anti-CD3 antibodies.

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Allelic Variation of Ets1 Does Not Contribute to NK and NKT Cell Deficiencies in Type 1 Diabetes Susceptible NOD Mice

Margaret A. Jordan¹, Lynn D. Poulton², Julie M. Fletcher¹, Alan G. Baxter¹

Abstract

The NOD mouse is a well characterized model of type 1 diabetes that shares several of the characteristics of Ets1-deficient targeted mutant mice, viz: defects in TCR allelic exclusion, susceptibility to a lupus like disease characterized by IgM and IgG autoantibodies and immune complex-mediated glomerulonephritis, and deficiencies of NK and NKT cells. Here, we sought evidence for allelic variation of Ets1 in mice contributing to the NK and NKT cell phenotypes of the NOD strain. ETS1 expression in NK and NKT cells was reduced in NOD mice, compared to C57BL/6 mice. Although NKT cells numbers were significantly correlated with ETS1 expression in both strains, NKT cell numbers were not linked to the Ets1 gene in a first backcross from NOD to C57BL/6 mice. These results indicate that allelic variation of Ets1 did not contribute to variation in NKT cell numbers in these mice. It remains possible that a third factor not linked to the Ets1 locus controls both ETS1 expression and subsequently NK and NKT cell phenotypes.

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Comparison of Fasting Glucose with Post-Load Glucose Values and Glycated Hemoglobin for Prediction of Type 2 Diabetes: The Isfahan Diabetes Prevention Study

Mohsen Janghorbani^1,2, Masoud Amini²

Abstract

OBJECTIVES: The aim of this study was to compare the ability of fasting plasma glucose (FPG), post-load plasma glucose values and glycated hemoglobin (HbA1c) to predict progression to diabetes in non-diabetic first-degree relatives (FDR) of patients with type 2 diabetes. METHODS: A total of 701 non-diabetic FDR of diabetic patients aged 20-70 years surveyed in 2003 to 2005 were followed until 2008 for the onset of type 2 diabetes mellitus. At baseline and at follow-ups, participants underwent a standard 75 g 2-hour oral glucose tolerance test (OGTT). Prediction of progression to type 2 diabetes was assessed by using area under the receiver-operating characteristic (ROC) curves based upon measurement of FPG, post-load glucose values and HbA1c. RESULTS: The incidence of type 2 diabetes was 33.9 per 1000 person-years in men and 48.6 in women. The incidence rates were 4.6, 50.7, and 99.7 per 1000 person-years in FDR with normal glucose tolerance, impaired fasting glucose and impaired glucose tolerance respectively. FPG value was a better predictor of progression to diabetes than any post-load glucose values or HbA1c. The areas under the ROC curves were 0.811 for fasting, 0.752 for 1/2-hour, 0.782 for 1-hour and 0.756 for 2-hour glucose vs. 0.634 for HbA1c (p < 0.001). CONCLUSIONS: FPG had more discriminatory power to distinguish between individuals at risk for diabetes and those who were not at risk than post-load glucose values during OGTT or HbA1c. Our findings support the American Diabetes Association recommendation of using FPG concentration to diagnose diabetes.

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Prevalence of Diabetic Retinopathy and Cataract in Adult Patients With Type 1 And Type 2 Diabetes in Russia

Ivan Dedov, Oxana Maslova, Yurii Suntsov, Lubov Bolotskaia, Tamara Milenkaia, Lena Besmertnaia

Abstract

AIM: The aim of the study was to identify the prevalence of diabetic retinopathy (DR) and diabetic cataract (DC) in type 1 and type 2 diabetic patients within the Russian Federation. Also, the stage of DR at the time of its identification and the proportion of new cases diagnosed with DR or DC were to be determined. METHODS: A random sample of 7,186 adult patients with diabetes was screened for DR and DC using fundoscopy and fundus photography. Levels of HbA1c, total cholesterol, triglycerides, creatinine and urinary albumin excretion rate were assessed. RESULTS: In diabetic patients, the prevalence of DR and DC was 45.9% and 30.6%, respectively. These complications appeared significantly more frequently in patients with type 1 diabetes than in type 2 diabetes. The prevalence of background, preproliferative and proliferative DR among diabetic patients was 28.1%, 8.1%, and 6.7%, respectively. Patients with DR were older, had a longer duration of diabetes, higher HbA1c, elevated plasma total cholesterol, increased triglicerides, and higher systolic BP, compared with patients without DR. Microalbuminuria and proteinuria were more prevalent among patients with DR compared with non-DR patients. CONCLUSIONS: The results showed that diabetic retinopathy and cataract are wide-spread complications among diabetic patients in Russia. However, the disease course is more aggressive and accelerated in patients with type 1 diabetes than in those having type 2 diabetes. Therefore, it is important to prevent DR by identifying diabetes and signs of retinopathy at the earliest possible stage of progression for timely and adequate retina laser coagulation or surgical treatment, compensation of carbohydrate and lipid metabolism, and normalization of blood glucose and pressure.

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