Anne Kaas

Gluten‐free diet prevents diabetes in NOD mice

Epidemiological as well as animal studies have shown that environmental factors such as nutrition contribute to the development of diabetes. In this study we investigated whether the early introduction of a gluten‐free diet can influence the onset and/or incidence of diabetes, as well as insulitis and the number of gut mucosal lymphocytes, in non‐obese diabetic (NOD) mice.

Diabetes preventive gluten-free diet decreases the number of caecal bacteria in non-obese diabetic mice

A gluten‐free diet reduces the incidence of diabetes mellitus in non‐obese diabetic (NOD) mice, but the mechanism is not known. The aim of this study was to examine the possible influence of the diet on the caecal bacterial flora, which may affect the intestinal physiology and mediate disease prevention.

Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes

Environmental factors such as nutrition or exposure to infections play a substantial role in the pathogenesis of type 1 diabetes (T1D). We have previously shown that gluten‐free, non‐purified diet largely prevented diabetes in non‐obese diabetic (NOD) mice. In this study we tested hypothesis that early introduction of gluten‐enriched (gluten+) diet may increase diabetes incidence in NOD mice.

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes.

Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longitudinally circulating concentrations of CCR5 ligands of 256 newly diagnosed patients with type 1 diabetes. CCR5 ligands were differentially associated with beta-cell function and clinical remission. CCL5 was decreased in remitters and positively associated with HbA1c suggestive of a Th1 associated progression of the disease. Likewise, CCL3 was negatively related to C-peptide and positively associated with the beta-cell stress marker proinsulin but increased in remitters. CCL4 associated with decreased beta-cell stress shown by negative association with proinsulin. Blockage of chemokines or antagonism of CCR5 by therapeutic agents such as maraviroc may provide a new therapeutic target to ameliorate disease progression in type 1 diabetes.

Patients with Insulin-dependent Diabetes but not those with Non-insulin-dependent Diabetes have Anti-sulfatide Antibodies as Determined with a New ELISA Assay

Background: In sera from newly diagnosed insulin-dependent diabetes mellitus patients (IDDM type 1) autoantibodies occur against different antigen determinants often shared with neural tissues. The role of these autoantibodies in the disease process is not yet clarified but they can be used as a diagnostic tool in the detection of IDDM patients. Methods: We have analysed the occurrence of sulfatide autoantibodies in serum from patients with type 1 diabetes (n = 20), individuals with pre-type 1 diabetes (n = 6), patients with type 2 diabetes (n = 32) and controls (n = 43). The method used for the determination of the autoantibodies was a newly developed microtitre-ELISA assay utilizing a complex of sulfatide-albumin as the ligand. Results: The new assay procedure for serum sulfatide autoantibodies showed good reproducibility. The total (day-to-day) imprecision based on analyses of three different serum samples with positive titres varied between 11 and 14% during an assay period of 6 months. None of the controls (0/43) had positive titres of sulfatide antibodies. Of the patients with type 1 diabetes, 85% displayed positive titres of anti-sulfatide antibodies while none of the type 2 patients did so. All individuals with pre-type 1 diabetes had positive titres of sulfatide antibodies. Conclusions: We conclude that sulfatide autoantibodies in serum can be reproducibly assayed by the newly developed microtitre-ELISA procedure. Elevated titres of sulfatide autoantibodies are a constant finding in newly diagnosed type 1 patients.

Association between age, IL-10, IFNγ, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes.

Diabet. Med. 29, 734–741 (2012)

Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes

Kaas A, Max Andersen ML, Fredheim S, Hougaard P, Buschard K, Petersen JS, de Beaufort C, Robertson KJ, Hansen L, Mortensen HB, Nielsen LB, On behalf of The Hvidoere Study Group on childhood diabetes. Proinsulin, GLP‐1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes.

Effect of intrathymic administration of mycobacterial heat shock protein 65 and peptide p277 on the development of diabetes in NOD mice: caution required in vaccination studies

Heat shock protein 65 (hsp65) and a derived peptide, p277, are autoantigens reported in IDDM. I.p. injection of hsp65 reduced diabetes incidence in NOD mice and administration of p277 cured already diabetic mice. Also, intrathymic (i.t.) administration of whole islets or GAD65 prevented diabetes in NOD mice. The aim of this study was to evaluate whether i.t. injection of mycobacterial hsp65 or p277 can prevent diabetes in NOD mice. Three‐week‐old NOD female mice were injected intrathymically with 50 μg of hsp65 (n=30), 5 μg of p277 (n=30), and PBS (n=29). Diabetes incidence was observed for the following 300 days. Pancreas was then used for histological and immunohistological evaluation. No significant differences in diabetes incidence were observed among the three groups of mice. Interestingly, hsp65‐treated mice developed diabetes slightly faster at 177±6 days compared to 202±8 days (p=0.015) for the p277‐treated group and 197±7 days (p=0.033) for controls. The insulitis score and average islet size did not differ significantly among the three groups of diabetic mice. Scattered TCR‐gamma/delta positive cells were found in the pancreas of all groups of mice. In contrast, a huge infiltrate of TCR‐gamma/delta positive cells was detected in four out of eight (50%) p277‐diabetic NOD mice. Thus, our data show an earlier onset of diabetes in hsp65‐treated mice and no improvement in the incidence with either hsp65 or p277, suggesting that hsp65 acts in a different way from what was reported with GAD65. Caution is advised in future vaccination studies as hsp65 poses a potential danger.

Evaluation of a type 1 diabetes serum cohort by SELDI-TOF MS protein profiling.

Proteomics analysis of serum from patients with type 1 diabetes (T1D) may lead to novel biomarkers for prediction of disease and for patient monitoring. However, the serum proteome is highly sensitive to sample processing and before proteomics biomarker research serum cohorts should preferably be examined for potential bias between sample groups.

Developmental expression of the type I diabetes related antigen sulfatide and sulfated lactosylceramide in mammalian pancreas.

Previous studies have shown that sulfatide is present and functionally involved in beta cells, and that anti‐sulfatide antibodies (ASA) exist during development of type I diabetes mellitus. To further explore the possible role of sulfatide in type I diabetes, developmental expression was examined in human pancreas and in pancreas of the type I diabetes models BB rat and NOD mouse compared to Lewis rat and BALB/c mouse, respectively. Sulfatide was not only expressed in adult pancreas, but also in human fetal and rodent neonatal pancreas, i.e., during the growing period of the immunological self. Sulfatide had a different expression pattern in human beings and rodents, concerning both the amounts of sulfatide and expression during development. There was no change in the sulfatide fatty acid isoform expression during development. The pancreatic expression of another sulfated glycosphingolipid, sulfated lactosylceramide, indicated that this molecule is a potential fetal/neonatal marker, which was further expressed in the type I diabetic models. In conclusion, these findings give further support to the possibility that sulfatide is a relevant autoantigen in type I diabetes and that sulfated lactosylceramide might function as a potential risk factor for disease development, at least in the animal models. J. Cell. Biochem. 89: 301–310, 2003.