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  • 1.
    Axelsson, Stina
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65)2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 7, p. 559-568Article in journal (Refereed)
    Abstract [en]

    Background We have previously shown that two injections of 20 mu g alum-formulated glutamic acid decarboxylase 65 (GAD(65)) (GAD-alum; Diamyd (R)) in children with recent-onset type 1 diabetes lead to preservation of residual insulin secretion. In vitro cytokine production at the 15 months follow-up indicated immunomodulation. In the present study, we took advantage of peripheral blood mononuclear cells, cryopreserved during early follow-ups, to investigate whether the immunomodulatory effect of GAD-alum was apparent earlier after treatment, preceding the changes previously reported at 15 months.<p>Methods Peripheral blood mononuclear cells from 70 type 1 diabetic children, randomly assigned GAD-alum (n = 35) or placebo (n = 35), that had been frozen at baseline (n = 27) and after 1 (n = 58), 3 (n = 67) and 9 (n = 66) months, were stimulated in vitro with GAD(65), tyrosine phosphatase-like protein IA-2 peptide, insulin peptide, GAD-alum, alum formulation or phytohaemagglutinin. Interleukin (IL)-5, -6, -10, -12, -13, -17, tumour necrosis factor and interferon-gamma were measured in cell supernatants and serum samples using Luminex. Expression of FOXP3 and transforming growth factor-beta was determined by real-time reverse transcription polymerase chain reaction.</p><p>Results Already 1 month after the first injection, GAD(65)-induced IL-5 and IL-13 together with FOXP3 were enhanced in GAD-alum-treated patients compared to those with placebo. The in vitro response at 3 and 9 months was characterized by a broader range of cytokines in the treated group. Notably, only the T-helper 2-associated cytokines IL-5 and IL-13 together with FOXP3 increased continuously over time.</p><p>Conclusions Treatment with GAD-alum in type 1 diabetic children induced an early T-helper 2 immune enhanced response to GAD(65), followed by a wider spectrum of cytokines at 3 and 9 months. Copyright (C) 2010 John Wiley &amp; Sons, Ltd.</p>

  • 2.
    Christensen, Michael
    et al.
    Aarhus Univ, Denmark.
    Schiffer, Tomas A.
    Uppsala Univ, Sweden.
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Norrköping/Finspång.
    Palmelund Krag, Soren
    Aarhus Univ Hosp, Denmark.
    Norregaard, Rikke
    Aarhus Univ, Denmark.
    Palm, Fredrik
    Uppsala Univ, Sweden.
    Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-22019In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 35, no 2, article id e3091Article in journal (Refereed)
    Abstract [en]

    Background The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis. Methods Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance. Results Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats. Conclusions Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.

  • 3.
    Dietrich, Fabricia
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Barcenilla, Hugo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Tavira Iglesias, Beatriz
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlberg, Jeanette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology. Faculty of Medical Sciences, Örebro University, Örebro, Sweden.
    Achenbach, Peter
    Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany; .
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Casas, Rosaura
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Immune response differs between intralymphatic or subcutaneous administration of GAD-alum in individuals with recent onset type 1 diabetes2022In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 38, no 3, article id e3500Article in journal (Refereed)
    Abstract [en]

    Aims: Immunomodulation with autoantigens potentially constitutes a specific and safe treatment for type 1 diabetes (T1D). Studies with GAD-alum administrated subcutaneously have shown to be safe, but its efficacy has been inconclusive. Administration of GAD-alum into the lymph nodes, aimed to optimise antigen presentation, has shown promising results in an open-label clinical trial. Herein, we compared the immune response of the individuals included in the trial with a group who received GAD-alum subcutaneously in a previous study.

    Materials and methods: Samples from T1D individuals collected 15 months after administration of either three doses 1 month apart of 4 mu g GAD-alum into lymph nodes (LN, n = 12) or two doses 1 month apart of 20 mu g subcutaneously (SC, n = 12) were studied. GADA, GADA subclasses, GAD(65)-induced cytokines, peripheral blood mononuclear cell proliferation, and T cells markers were analysed.

    Results: Low doses of GAD-alum into the lymph nodes induced higher GADA levels than higher doses administrated subcutaneously. Immune response in the LN group was characterised by changes in GADA subclasses, with a relative reduction of IgG1 and enhanced IgG2, IgG3, and IgG4 proportion, higher GAD(65)-induced secretion of IL-5, IL-10, and TNF-alpha, and reduction of cell proliferation and CD8(+) T cells. These changes were not observed after subcutaneous (SC) injections of GAD-alum.

    Conclusions: GAD-specific immune responses 15 months after lymph node injections of GAD-alum differed from the ones induced by SC administration of the same autoantigen.

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  • 4.
    Edlund, Jenny
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Integrativ Fysiologi.
    Liss, Per
    Uppsala universitet, Enheten för radiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    The roles of NADPH-oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 5, p. 349-356Article in journal (Refereed)
    Abstract [en]

    Background

    Sustained hyperglycaemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We investigated the roles of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and the neuronal nitric oxide synthase (nNOS) for the increased oxygen consumption in streptozotocin-diabetic rats.

    Methods

    Oxygen consumption was measured in isolated proximal tubular cells (PTC) from streptozotocin-induced diabetic rats (n = 7-9 per group) with and without chronic treatment with apocynin, a NADPH-oxidase inhibitor, or S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycaemic controls (n = 10). Oxidative stress was estimated from thiobarbituric acid reactive substances and protein expression measured by Western blot.

    Results

    Proximal tubular cells from untreated diabetic rats had increased oxygen consumption compared to controls (40.6 +/- 7.9 versus 10.9 +/- 2.0 nmol/mg protein/min). All treatments reduced the diabetes-induced increase in oxygen consumption (apocynin 10.5 +/- 1.7, SMTC 19.7 +/- 3.0 and apocynin +/- SMTC 21.6 +/- 3.6 nmol/mg protein/min). Neither apocynin nor SMTC had any effect on the oxygen consumption in cells pre-incubated with ouabain, an inhibitor of active electrolyte transport. Oxidative stress was elevated in the diabetic kidney and inhibited by all treatments. The increased oxygen consumption by diabetic proximal tubular cells correlated with increased protein expressions of p47phox and nNOS and the treatments prevented these increases.

    Conclusions

    Diabetes induces oxidative stress, which increases oxygen consumption in proximal tubular cells. Inhibition of either NADPH-oxidase or nNOS prevented the increased oxygen consumption. The effect of blocking both these enzymes was less than additive suggesting overlapping pathways which warrant further studies.

  • 5.
    Honkanen, Jarno
    et al.
    Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
    Skarsvik, Susanne
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Knip, Mikael
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland and Department of Paediatrics, Tampere University Hospital, Tampere, Finland.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Poor in vitro induction of FOXP3 and ICOS in type 1 cytokine environment activated T-cells from children with type 1 diabetes2008In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 24, no 8, p. 635-641Article in journal (Refereed)
    Abstract [en]

    Background

    Type 1 diabetes (T1D) is characterised by loss of tolerance to beta-cell antigens, and the insulin-producing beta-cells in the pancreatic islets are destroyed by the host's own immune system. Immunological risk factors associated with T1D are related to the defects in the polarization of T-cells and in the function of regulatory T (Treg)-cells. We set out to study whether an impaired induction of regulatory mechanisms during the generation of T-cell responses upon stimulation is associated with T1D.

    Methods

    Naive T-cells were isolated from 18 children with recent T1D (0–14days from diagnosis; mean age 9.3 years), 11 children who had had T1D for at least 1 year (mean age 10.6) and 14 non-diabetic children (mean age 8.1). CD45RA+ T-cells were stimulated with PHA for 72 h in type 1 cytokine [interleukin (IL)-12 and anti-IL-4] or type 2 cytokine (IL-4 and anti-IL-12) environment. T-cell polarization and regulation related markers were analysed by quantitative reverse transcription polymerase chain reaction (QRT-PCR) (Th1 promoting T-bet, Th2 promoting GATA-3 and regulation related FOXP3, ICOS and NFATc2).

    Results

    Children with recently diagnosed T1D showed decreased induction of FOXP3, ICOS and NFATc2 in T-cells activated in type 1 cytokine milieu (p = 0.007, p = 0.001, and p = 0.02), whereas no differences between the diabetic and healthy children were seen in the up-regulation of activation markers, T-bet and GATA-3.

    Conclusions

    The poor induction of factors that mediate down-modulation of T-cell responses upon stimulation in type 1 cytokine environment may contribute to the development of autoreactive type 1 responses in T1D.

  • 6.
    Karlsson Faresjö, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Thuswaldner, Sophie
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    JDRF Center for Prevention of Type 1 Diabetes in Finland and the Department of Virology, University of Turku, Turku, Finland.
    Hinkkanen, Ari
    Åbo Akademi, Turku University, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Diminished IFN-γ response to diabetes-associated autoantigens in children at diagnosis and during follow up of type 1 diabetes2006In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 22, no 6, p. 462-470Article in journal (Refereed)
    Abstract [en]

    Background

    Imbalance of T-helper (Th)1- and Th2-like cytokines has been associated with type 1 diabetes. We therefore studied the immune deviation in antigen-specific T cells from diagnosis onwards in type 1 diabetic children.

    Methods

    Peripheral blood mononuclear cells (PBMC) were collected from 15 children after 4 days, 3 months and 18 months of being diagnosed with type 1 diabetes, from 15 healthy children matched by age and gender to the type 1 diabetic children and from 14 children with and 35 children without HLA-risk genes. Secretion of interferon-γ (IFN-γ) and interleukin-4 (IL-4) was detected by ELISPOT after stimulation with glutamic acid decarboxylase (GAD65, protein and aa 247–279), recombinant tyrosinphosphatase (IA-2), insulin, ovalbumin and phytohaemagglutinin (PHA).

    Results

    Secretion of IFN-γ in PBMC stimulated with GAD65 (p < 0.05), the GAD65-peptide (p < 0.01), IA-2 (p < 0.01), and insulin (p < 0.01) was lower in diabetic children at diagnosis than in healthy children. Stimulation of PBMC with GAD65 and IA-2 decreased the secretion of IFN-γ in children with HLA-risk genotype. Spontaneous and antigen-induced IFN-γ secretion increased significantly after diagnosis of the disease, but did not exceed the levels observed in healthy children. Fasting C-peptide levels at diagnosis correlated with insulin-induced IFN-γ (R = 0.52; p = 0.05) and negatively with spontaneous IL-4 secretion (R = −0.62; p < 0.05).

    Conclusion

    A diminished IFN-γ secretion and the association of fasting C-peptide levels with cytokine response in children with type 1 diabetes suggest that factors related to β-cell function in type 1 diabetes may modify T-cell function. Thus, the T-cell responses detected at or after diagnosis may not reflect the pathogenic process leading to type 1 diabetes.

  • 7. Lindahl, Emma
    et al.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Müller, Patrick
    El Agha, Eli
    Friederich, Malou
    Uppsala universitet, Integrativ Fysiologi.
    Dahlman-Wright, Karin
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Jörnvall, Hans
    Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells2011In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 7, p. 697-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.

  • 8.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    C-peptide an adequate endpoint in type 1 diabetes2009In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 8, p. 691-693Article in journal (Other academic)
    Abstract [en]

    n/a

  • 9.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Therapy with GAD in diabetes2009In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, p. 307-315Article, review/survey (Refereed)
    Abstract [en]

    The enzyme glutamic acid decarboxylase (GAD) is of great importance for the neurotransmission in the central nervous system, and therefore of interest for treatment of pain and neurological disease. However, it is also released in pancreas although its role is not quite clear. GAD is a major auto-antigen in the process leading to type 1 diabetes with both a clear cell-mediated immune response to GAD and auto-antibodies to GAD (GADA), which call be used as a predictor of diabetes. Administration of the isoform GAD65 can prevent autoimmune destruction of pancreatic beta cells in non-obese diabetic (NOD) mice and the subsequent need for exogenous insulin replacement. In Phase I and II studies an alum-formulated vaccine (Diamyd) has shown to be safe, and in a dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients 20-mu g was given subcutaneously one month apart indicating preservation of residual insulin secretion. A double-blind randomized Phase II trial in 70 patients (10-18 years old) with recent-onset type 1 diabetes showed significant preservation of residual insulin secretion and a GAD-specific immune response, both humoral and cell-mediated, but no treatment-related adverse events. With this promising background further studies are on their way, both intervention in newly diagnosed type 1 diabetic patients, and trials to prevent the disease.

  • 10.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months2014In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 30, no 5, p. 405-414Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This study aimed to analyse data from two different studies (Phase II and Phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum), 30 months after administration to children and adolescents with Type 1 diabetes (T1D).

    METHODS: The Phase II trial was a double-blind, randomized placebo-controlled study, including 70 children and adolescents which were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and one month later. During a subsequent larger European Phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The Phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up and 45 patients completed the trial at 30 months. Both studies included GADA-positive patients with fasting C-peptide ≥0.10 nmol/l. We have now combined the results of these two trials.

    RESULTS: There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide AUC had decreased significantly less (9 m: p < 0.037; 15 m p < 0.032; 21 m p < 0.003 and 30 m p < 0.004) and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide >0.2 nmol/l (p < 0.05), as compared to placebo.

    CONCLUSION: Treatment with two doses of GAD-alum in children and adolescents with recent-onset T1D shows no adverse events and preserves residual insulin secretion. This article is protected by copyright. All rights reserved.

  • 11.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Holmqvist, Britt-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Does modern high standard life style cause type 1 diabetes in children?2013In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 29, no 2, p. 161-165Article in journal (Refereed)
    Abstract [en]

    Background Type 1 diabetes is a serious disease which, in spite of intensive treatment, causes serious complications and increased mortality. The incidence is increasing, but the aetiology is unknown. As part of modern lifestyle, increased hygiene has been suspected as one contributing cause but so far there is no evidence. Several large epidemiological studies, mainly restricted to children with increased genetic risk for type 1 diabetes, have so far given no clue. Methods All Babies in Southeast Sweden is unique in its design as it has followed an unselected group of children from birth 19971999 and onwards with regular follow-ups. This report is based on questionnaires from initially 16051 children of whom 80 have later on developed type 1 diabetes. The parents answered questionnaires at the birth of their child and then after 1, 23, 56 and 8years. A number of parameters possibly related to hygiene were analysed with several statistical methods, both with univariate and in regression models. Results Our study cannot identify any crucial environmental factor. This indicates that hygiene-related parameters traditionally regarded as part of modern life style do not play any important role for the aetiology of type 1 diabetes. Conclusions There is no reason to recommend a change of that part of our lifestyle. We find weak associations to previous gastrointestinal infections, which gives a hint that development of type 1 diabetes may be related to problems in the gut and maybe one should look closer into the microbes living in the gut.

  • 12.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Routray, Indusmita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Vigard, Tore
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Hanas, Ragnar
    NU Hosp Grp, Sweden; Univ Gothenburg, Sweden.
    Rathsman, Bjorn
    Sachska Pediat Hosp, Sweden.
    Carlsson, Annelie
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Sarnblad, Stefan
    University Hospital, Örebro, Swede.
    Albin, Anna-Karin
    Helsingborg Cent Hosp, Sweden.
    Arvidsson, Carl-Goran
    Vasteras Hosp, Sweden.
    Samuelsson, Ulf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Casas, Rosaura
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes2021In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 37, no 7, article id e3440Article in journal (Refereed)
    Abstract [en]

    Aim

    We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD‐alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function.

    Material and Methods

    Etanercept Diamyd Combination Regimen is an open‐labelled multi‐centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3–16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C‐peptide was 0.24 ± 0.1 (0.10–0.35) nmol/l. The patients received Day 1‐450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1‐90 0.8 mg/kg once a week and GAD‐alum sc injections (20 μg, Diamyd™) Day 30 and 60. They were followed for 30 months.

    Results

    No treatment related serious adverse events were observed. After 6 months 90‐min stimulated C‐peptide had improved in 8/20 patients and C‐peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65‐induced TNF‐α increased. Spontaneous interleukin‐17a secretion increased after the administration of Etanercept, and GAD65‐induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration.

    Conclusions

    Combination therapy with parallel treatment with GAD‐alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.

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  • 13.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Samuelsson, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Johansson, C
    Stenhammar, Lars
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Treatment with antioxidants at onset of type 1 diabetes in children: a randomized, double-blind placebo-controlled study.2001In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 17, p. 131-136Article in journal (Refereed)
  • 14.
    Nguyet Pham, Minh
    et al.
    University of Dusseldorf, Germany .
    Kolb, Hubert
    University of Dusseldorf, Germany .
    Mandrup-Poulsen, Thomas
    University of Copenhagen, Denmark .
    Battelino, Tadej
    University of Childrens Hospital, Slovenia .
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Pozzilli, Paolo
    University of Campus BioMed, Italy .
    Roden, Michael
    University of Dusseldorf, Germany .
    Schloot, Nanette C.
    University of Dusseldorf, Germany .
    Serum adipokines as biomarkers of beta-cell function in patients with type 1 diabetes: positive association with leptin and resistin and negative association with adiponectin2013In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 29, no 2, p. 166-170Article in journal (Refereed)
    Abstract [en]

    Background We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes. Methods One hundred and eighteen patients with type 1 diabetes (20.3 +/- 7.5years) diagnosed andlt;5years underwent standardized mixed meal test (MMTT) for 2h. Systemic concentrations of C-peptide, adiponectin, leptin and resistin obtained during MMTT were measured and compared between patient groups by multiple regression analysis. Results Patients were divided by their adipokine levels in subgroups above or below the median level (high versus low). High adiponectin levels (andgt;10.6 mu g/mL) were associated with lower C-peptide compared to the low adiponectin subgroup (pandlt;0.03). Increased leptin or resistin concentrations associated positively with beta-cell function even after adjustment for metabolic confounders (pandlt;0.04). The described associations between adipokines and C-peptide concentrations persisted in Spearman correlation tests (pandlt;0.05). Serum adipokines fell during MMTT (pandlt;0.05). Conclusions Serum adipokine levels differentially correlate with beta-cell function in type 1 diabetes independent of BMI or metabolic control. Serum adipokines should be investigated as biomarkers of beta-cell function in prospective studies and intervention trials in type 1 diabetes.

  • 15.
    Nordwall, Maria
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Norrköping.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Clinical manifestations and beta cell function in Swedish diabetic children have remained unchanged during the last 25 years2008In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 24, no 6, p. 472-479Article in journal (Refereed)
    Abstract [en]

    Background: The incidence of type 1 diabetes in childhood has doubled in Sweden during the last decades. Environmental factors may cause a different disease process, residual beta cell function and clinical manifestation. Insulin therapy has become more intensive. The aim of this study was to examine the clinical characteristics at onset C-peptide secretion during the first years, after diagnosis and if there was any secular trends during the last 25 years.

    Methods: All 316 children diagnosed with type 1 diabetes during 1976-2000 and living in the Linkoping area were included. Information about clinical characteristics at diagnosis, duration of partial remission, insulin therapy at diagnosis and during the first years was collected from medical records. C-peptide secretion (fasting and stimulated) was measured regularly during the first 5 years. For analysis, the population was divided in five cohorts according to the year of diagnosis.

    Results: The clinical characteristics at onset were unchanged as well as duration of partial remission. C-peptide secretion was highest after 3 months and then declined gradually. After 5 years 32.7% of the patients had measurable fasting C-peptide, but only 6.5% >0.1 nmol/L. HbA(1c) and insulin doses were lower in patients with persistent fasting C-peptide secretion >0.1 nmol/L. The cohort 1996-2000 had higher stimulated C-peptide secretion at diagnosis and at 3 months, after longer follow-up there was no difference.

    Conclusion: The clinical characteristics at diagnosis, partial remission and duration of C-peptide secretion have remained largely unchanged for the last 25 years.

     

  • 16.
    Papadopoulou-Marketou, Nektaria
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology. University of Athens, Greece.
    Chrousos, George P.
    University of Athens, Greece.
    Kanaka-Gantenbein, Christina
    University of Athens, Greece.
    Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis2017In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 33, no 2, article id e2841Article, review/survey (Refereed)
    Abstract [en]

    Diabetic nephropathy constitutes a devastating complication in patients with type 1 diabetes mellitus, and its diagnosis is traditionally based on microalbuminuria. The aim of this review is to update through the medical literature the suggested early natural course of diabetic nephropathy, the theories behind the pathways of its pathogenesis, and its diagnosis. Poor glycemic control, dyslipidemia, smoking, advanced glycation end products, and environmental and genetic clues play an important role in the development of diabetic nephropathy. Microalbuminuria has been traditionally considered as a primary early marker of microvascular complication unraveling the risk for progress to the advanced stages of chronic kidney disease, but because of our inability to make an early diagnosis of diabetic nephropathy in young patients as well as nonalbuminuric diabetic nephropathy, recently, other additional markers of renal injury like serum and urinary neutrophil gelatinase-associated lipocalin, chitinase-3-like protein 1, cystatin C, and plasma growth differentiation factor 15 have been proposed to unmask early renal dysfunction, even before microalbuminuria supervenes. Copyright (C) 2016 John Wiley amp; Sons, Ltd.

  • 17.
    Ping Zhao, Lue
    et al.
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98195 USA.
    Carlsson, Annelie
    Lund University, Sweden.
    Elding Larsson, Helena
    Lund University, Sweden.
    Forsander, Gun
    Sahlgrens University Hospital, Sweden.
    Ivarsson, Sten A.
    Lund University, Sweden.
    Kockum, Ingrid
    Karolinska Institute, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Marcus, Claude
    Karolinska Institute, Sweden.
    Persson, Martina
    Karolinska University Hospital, Sweden.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Ortqvist, Eva
    Karolinska University Hospital, Sweden.
    Pyo, Chul-Woo
    Fred Hutchinson Cancer Research Centre, WA 98104 USA.
    Bolouri, Hamid
    University of Washington, WA 98195 USA.
    Zhao, Michael
    University of Washington, WA 98195 USA.
    Nelson, Wyatt C.
    Fred Hutchinson Cancer Research Centre, WA 98104 USA.
    Geraghty, Daniel E.
    Fred Hutchinson Cancer Research Centre, WA 98104 USA.
    Lernmark, Ake
    Lund University, Sweden.
    Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes2017In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 33, no 8, article id e2921Article in journal (Refereed)
    Abstract [en]

    AimIt is of interest to predict possible lifetime risk of type 1 diabetes (T1D) in young children for recruiting high-risk subjects into longitudinal studies of effective prevention strategies. MethodsUtilizing a case-control study in Sweden, we applied a recently developed next generation targeted sequencing technology to genotype class II genes and applied an object-oriented regression to build and validate a prediction model for T1D. ResultsIn the training set, estimated risk scores were significantly different between patients and controls (P=8.12x10(-92)), and the area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was 0.917. Using the validation data set, we validated the result with AUC of 0.886. Combining both training and validation data resulted in a predictive model with AUC of 0.903. Further, we performed a biological validation by correlating risk scores with 6 islet autoantibodies, and found that the risk score was significantly correlated with IA-2A (Z-score=3.628, Pamp;lt;0.001). When applying this prediction model to the Swedish population, where the lifetime T1D risk ranges from 0.5% to 2%, we anticipate identifying approximately 20 000 high-risk subjects after testing all newborns, and this calculation would identify approximately 80% of all patients expected to develop T1D in their lifetime. ConclusionThrough both empirical and biological validation, we have established a prediction model for estimating lifetime T1D risk, using class II HLA. This prediction model should prove useful for future investigations to identify high-risk subjects for prevention research in high-risk populations.

  • 18.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Bolmeson, Caroline
    Cellular Autoimmunity Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Jonson, Carl-Oscar
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Cilio, Corrado M.
    Cellular Autoimmunity Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children2012In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 28, no 1, p. 84-96Article in journal (Refereed)
    Abstract [en]

    High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full length CTLA-4 and other Treg associated markers in T1D children and in individuals with high or low risk of developing the disease.

    T1D children were studied at four days, one and two years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells (PBMC) were stimulated with the T1D-associated glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA). Subsequently, soluble CTLA-4, full length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.

    Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel to a negative relation in healthy subjects. Further, low mitogen-induced soluble CTLA-4 was accompanied by low C-peptide, together indicating an inverse relation of soluble CTLA-4 between health and disease. Moreover, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high-risk individuals, indicating an alteration in activation and downregulating immune mechanisms already during the pre-diabetic phase.

  • 19.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Stechova, Katerina
    Charles University Prague.
    Durilova, Marianna
    Charles University Prague.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes2009In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, p. 335-343Article in journal (Refereed)
    Abstract [en]

    Background: Type 1 diabetes (T1D) is all autoimmune disease dominated by loss of self-tolerance resulting in depletion of the beta-cells. This Study aims to confirm previous observations of a dominant T-helper (Th)1-like profile during the period close to onset of disease. Further, to follow the immune response from onset to 2 years duration, the Study focused on spontaneous as well as autoantigen-induced immune profile.

    Methods: Peripheral blood mononuclear cells were collected 4 days and 1 and 2 years after diagnosis of T1D children, from healthy children carrying the human leukocyte antigen-risk genes and from high-risk children (ICA andgt;= 20 IJDF units). Peripheral blood mononuclear cells were stimulated with glutamic acid decarboxylase (GAD(65)) and phytohaemagglutinin (PHA). Cytokines and chemokines were detected in cell-culture supernatants by protein microarray (naive T-cells; interleukin (IL)-7, Th1; interferon-gamma, turnout necrosis factor-beta, Th2; IL-5, Th3; transforming growth factor-beta, T-regulatory cell type 1; IL-10 and inflammatory cytokines; tumour necrosis factor-alpha, IL-6 and chemokines; monocyte chemoattractant protein-1, monokine upregulated by IFN-gamma) in relation to clinical outcome (C-peptide).

    Results: High-risk children showed a dominant Th1-associated profile with high spontaneous and GAD(65)-induced secretion. The mitogen PHA instead induced a Th2-associated response exclusively in high-risk children. In contrast, newly diagnosed T1D children showed a pronounced Th3-associated cytokine profile as well as a burst of inflammatory cytokines and chemokines secreted both spontaneously and by GAD(65) and PHA stimulation. The immune response to GAD(65) and PHA, however, diminished with duration of disease.

    Conclusion: A dominant Thl-associated immune profile was observed during the pre-diabetic phase. This Th1 dominance, however, diminished in favour of a temporary increase in a Th3-associated and inflammatory immune profile at the onset of disease.

  • 20.
    Sadauskaite-Kühne, Vaiva
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Padaiga, Zilvinas
    Laboratory of Paediatric Endocrinology, Kaunas University of Medicine, Kaunas, Lithuania.
    Jasinskiene, Edita
    Laboratory of Paediatric Endocrinology, Kaunas University of Medicine, Kaunas, Lithuania.
    Samuelsson, Ulf
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood2004In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 20, no 2, p. 150-157Article in journal (Refereed)
    Abstract [en]

    Background

    Early weaning diet, early introduction of breast milk substitution and cow's milk have been shown to increase the risk of type 1 diabetes later in life. It is also shown that older maternal age, maternal education, preeclampsia, prematurity, neonatal illness and neonatal icterus caused by blood group incompatibility, infections and stress might be risk factors for type 1 diabetes. We aimed to determine whether early nutrition is an independent risk factor for diabetes despite other life events.

    Methods

    Data from 517 children (268 boys and 249 girls) in south-east of Sweden and 286 children (133 boys and 153 girls) in Lithuania in the age group of 0 to 15 years with newly diagnosed type 1 diabetes mellitus were included into analysis. Three age- and sex-matched healthy controls were randomly selected. Response rate in control families in Sweden was 72.9% and in Lithuania 94.8%. Information was collected via questionnaires.

    Results

    Exclusive breastfeeding longer than five months (odds ratio 0.54, 95% confidence interval 0.36–0.81) and total breastfeeding longer than 7 (0.56, 0.38–0.84) or 9 months (0.61, 0.38–0.84), breastfeeding substitution that started later than the third month (0.57, 0.33–0.98) among Swedish children 5 to 9 years old and later than the seventh month (0.24, 0.07–0.84) among all Swedish children is protective against diabetes when adjusted for all other above-listed risk factors. In Lithuania, exclusive breastfeeding longer than two months in the age group of 5 to 9 years is protective (0.58, 0.34–0.99) when adjusted for other factors.

    Conclusions

    Longer exclusive and total breastfeeding appears as an independent protective factor against type 1 diabetes.

  • 21.
    Samuelsson, Ulf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Lindblad, B
    Queen Silvia Children's Hospital, Sweden.
    Carlsson, A
    Lund University Hospital, Sweden.
    Forsander, G
    Queen Silvia Children's Hospital, Sweden.
    Ivarsson, S
    University Hospital MAS, Sweden.
    Kockum, I
    Karolinska Institute, Sweden.
    Lernmark, A
    Lund University, Sweden.
    Marcus, C
    Karolinska University Hospital, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season2013In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 29, no 1, p. 85-89Article in journal (Refereed)
    Abstract [en]

    Background

    There are seasonal variations and gender differences in incidence of type 1 diabetes (T1D), metabolic control and responses to immune interventions at onset of the disease.

    We hypothesized that there are seasonal and gender differences in residual insulin secretion already at diagnosis of T1D.

    Methods

    In 2005, a national study, the Better Diabetes Diagnosis, was started to classify all newly diagnosed children and adolescents with diabetes. About 95% (3824/4017) of the patients were classified as T1D, and our analyses are based on the patients with T1D.

    Results

    C-peptide was lower in younger children, 0–10 years of age (0.23 ± 0.20 nmol/L) than in older children, 11–18 years of age (0.34 ± 0.28 nmol/L) (p  < 0.000 ). There was a seasonal variation in non-fasting serum C-peptide, significantly correlated to the seasonal variation of diagnosis (p < 0.01). Most children were diagnosed in January, February and March as well as in October when C-peptide was highest, whereas fewer patients were diagnosed in April and May when serum C-peptide was significantly lower (p < 0.01). The seasonal variation of C-peptide was more pronounced in boys than in girls (p < 0.000 and p < 0.01, respectively). Girls had higher C-peptide than boys (p < 0.05), especially in early puberty.

    Conclusions

    Both seasonal and gender differences in residual beta cell function exist already at diagnosis of T1D. These observations have consequences for treatment and for randomizing patients in immune intervention clinical trials.

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  • 22. Stechova, Katerina
    et al.
    Bohmova, Kristyna
    Vrabelova, Zuzana
    Sepa, Anneli
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Stadlerova, Gabriela
    Zacharovova, Klara
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    High T-helper-1 cytokines but low T-helper-3 cytokines, inflammatory cytokines and chemokines in children with high risk of developing type 1 diabetes2007In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 23, no 6, p. 462-471Article in journal (Refereed)
    Abstract [en]

    Background. Type 1 diabetes (T1D) is suggested to be of T-helper (Th)1-like origin. However, recent reports indicate a diminished interferon (IFN)-γ secretion at the onset of the disease. We hypothesize that there is a discrepancy in subsets of Th-cells between children with a high risk of developing T1D, children newly diagnosed with T1D and healthy children. Methods. Peripheral blood mononuclear cells (PBMC) were collected from children at high risk for T1D (islet cells antibodies [ICA] ≥ 20 IJDF-U), those newly diagnosed and healthy children carrying the HLA-risk gene DQB1*0302 or DQB1*0201 and DQA1*0501. Th1- (IFN-γ, tumour necrosis factor [TNF]-β, interleukin [IL]-2), Th2- (IL-4,-5,-13), Th3- (transforming growth factor [TGF-β], IL-10) and inflammatory associated cytokines (TNF-α, IL-1α,-6) and chemokines (monocyte chemoattractant protein [MCP]-1,-2,-3, Monokine unregulated by IFN-γ [MIG], Regulated on Activation, Normal T-cell Expressed and Secreted [RANTES], IL-7,-8,-15) were detected in cell-culture supernatants of PBMC, stimulated with glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA), by protein micro array and enzyme linked immunospot (ELISPOT) technique. Results. The Th1 cytokines IFN-γ and TNF-β, secreted both spontaneously and by GAD65- and mitogen stimulation, were seen to a higher extent in high-risk children than in children newly diagnosed with T1D. In contrast, TNF-α and IL-6, classified as inflammatory cytokines, the chemokines RANTES, MCP-1 and IL-7 as well as the Th3 cytokines TGF-β and IL-10 were elevated in T1D children compared to high-risk children. Conclusion. High Th-1 cytokines were observed in children with high risk of developing TID, whereas in children newly diagnosed with T1D Th3 cytokines, inflammatory cytokines and chemokines were increased. Thus, an inverse relation between Th1-like cells and markers of inflammation was shown between children with high risk and those newly diagnosed with T1D. Copyright © 2007 John Wiley & Sons, Ltd.

  • 23.
    Strollo, Rocky
    et al.
    Univ Campus Biomed Roma, Italy.
    Vinci, Chiara
    Univ Campus Biomed Roma, Italy; Queen Mary Univ London, England.
    Napoli, Nicola
    Univ Campus Biomed Roma, Italy; IRCCS Ist Ortoped Galeazzi, Italy.
    Fioriti, Elvira
    Univ Campus Biomed Roma, Italy.
    Maddaloni, Ernesto
    Univ Campus Biomed Roma, Italy.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Pozzilli, Paolo
    Univ Campus Biomed Roma, Italy; Queen Mary Univ London, England.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Nissim, Ahuva
    Queen Mary Univ London, England.
    Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies2019In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, DIABETES-METABOLISM RESEARCH AND REVIEWS, Vol. 35, no 4, article id e3132Article in journal (Refereed)
    Abstract [en]

    Background

    Antibodies to posttranslationally modified insulin (oxPTM‐INS‐Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM‐INS‐Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB).

    Methods

    We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM‐INS‐Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA‐2A) in a cohort of islet AAB‐positive (AAB+) children from the general population (median follow‐up 8.8 years).

    Results

    oxPTM‐INS‐Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA‐2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM‐INS‐Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA‐2A (P = 0.896). oxPTM‐INS‐Ab and IA‐2A were more effective than IAA for detecting progr‐T1D when used as second‐line biomarker in GADA+ children. Risk for diabetes was higher (P = 0.03) among multiple AAB+ who were also oxPTM‐INS‐Ab+ compared with those who were oxPTM‐INS‐Ab–. Importantly, when replacing IAA with oxPTM‐INS‐Ab, diabetes risk increased to 100% in children with oxPTM‐INS‐Ab+ in combination with GADA+ and IA‐2A+, compared with 84.37% in those with IAA+, GADA+, and IA‐2A+ (P = 0.04).

    Conclusions

    Antibodies to oxidized insulin (oxPTM‐INS‐Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB+ children.

  • 24.
    Svensson, M. K.
    et al.
    University of Gothenburg, Sweden.
    Tyrberg, M.
    Lund University, Sweden.
    Nystrom, L.
    Umeå University, Sweden.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Bolinder, J.
    Karolinska Institute, Sweden.
    Ostman, J.
    Karolinska Institute, Sweden.
    Gudbjornsdottir, S.
    University of Gothenburg, Sweden.
    Landin-Olsson, M.
    Lund University, Sweden.
    Eriksson, J. W.
    Uppsala University, Sweden.
    The risk for diabetic nephropathy is low in young adults in a 17-year follow-up from the Diabetes Incidence Study in Sweden (DISS). Older age and higher BMI at diabetes onset can be important risk factors2015In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 31, no 2, p. 138-146Article in journal (Refereed)
    Abstract [en]

    AimsThe main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34years). MethodsAll 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes. ResultsAfter median 17years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1kg/m(2)), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p=0.041), BMI (p=0.012) and HbA1c (pless than0.001) were significant predictors of developing diabetic nephropathy between 9 and 17years of diabetes. At 17years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.051.12 per 1mmHg increase) were associated with DN. ConclusionsPatients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9years of follow-up was a risk marker for later development of diabetic nephropathy.

  • 25. Törn, Carina
    et al.
    Landin-Olsson, Mona
    Östman, Jan
    Scherstén, Bengt
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Blohmé, Göran
    Björk, Elisabeth
    Bolinder, Jan
    Eriksson, Jan
    Littorin, Bengt
    Nyström, Lennarth
    Sundkvist, Göran
    Lernmark, Åke
    Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds2000In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 16, no 6, p. 442-447Article in journal (Refereed)
    Abstract [en]

    Background Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes. Methods In a nationwide population-based study, blood samples were obtained from 764 patients, all diagnosed with diabetes during a 2-year period. At diagnosis, 583 (76%) were classified as Type 1, 110 (14%) as Type 2 and 71 (9.3%) could not be classified. Results Among patients not classified as Type 1 diabetes, 52 (47%) of Type 2 and 42 (59%) of unclassified patients were positive for islet cell antibodies CICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A). These patients (n=94) had lower body mass index (BMI) (p<0.001) and lower C-peptide (p<0.001) compared to the autoantibody negative patients (n=87). Compared to clinically classified Type 1 diabetes patients positive for autoantibodies (n=477), they have higher BMI (p<0.001), higher C-peptide (p<0.001) and the same levels of ICA, GADA and IA-2A. After 3 years, 93% of autoantibody positive patients initially not classified as Type 1 were on insulin. When ICA, GADA, IA-2A, BMI and C-peptide were tested in a multiple logistic regression, only GADA was signiificant for insulin treatment within 3 years (OR = 18.8, 95% CI 1.8-191) in patients treated with diet or oral drugs at diagnosis. Conclusions A correct classification is difficult in adult diabetic patients. The presence of pancreatic autoantibodies, especially GADA, at diagnosis of diabetes are highly predictive for insulin therapy within 3 years from diagnosis. Copyright ⌐ 2000 John Wiley & Sons, Ltd.

  • 26.
    Åkerman, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Swartling, Ulrica
    Lund University, Sweden.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Characteristics of the pre-diabetic period in children with high risk of type 1 diabetes recruited from the general Swedish populationThe ABIS study2017In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 33, no 6, article id e2900Article in journal (Refereed)
    Abstract [en]

    BackgroundThere is a need for increased understanding of the pre-diabetic period in individuals with high risk of type 1 diabetes from the general population. MethodsHigh-risk children (n=21) positive for multiple islet autoantibodies were identified by autoantibody screening within the All Babies in Southeast Sweden study. The children and their parents were enrolled in a 2-year prospective follow-up study aiming to characterize the pre-diabetic period. Blood samples were collected every 6months for measurement of C-peptide, HbA1c, fasting glucose, and autoantibodies. Human leukocyte antigen-genotype was determined, and oral glucose tolerance test was performed every 12months. ResultsDespite positivity for multiple autoantibodies, 9 out of 21 individuals had low-risk human leukocyte antigen-genotypes. Children who progressed to manifest diabetes (progressors, n=12) had higher levels of IA2A and ZnT8A than children who did not (non-progressors, n=9). Impaired glucose tolerance and impaired fasting glucose was observed to the same extent in progressors and non-progressors, but HbA1c increased over time in progressors in spite of increased C-peptide. ConclusionsAutoantibodies to IA2 and ZnT8 may be useful discriminators for disease progression in at-risk children from the general population. Dysglycemia was observed long before diagnosis, and difficulties in maintaining glucose homeostasis despite increased C-peptide indicate that insulin resistance might be an important accelerator of disease in risk individuals.

  • 27.
    Östgren, Carl-Johan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, General Practice. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland.
    Merlo, J
    Rastam, L
    lindblad, U
    Atrial fibrillation and its association with type 2 diabetes and hypertension in a Swedish community2004In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 6, no 5, p. 367-74Article in journal (Refereed)
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