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  • 1. Alvarsson, M
    et al.
    Sundkvist, G
    Lager, I
    Henricsson, M
    Berntorp, K
    Forbes, E
    Steen, L
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Orn, T
    Grill, V
    Different effects of withdrawal of insulin or glibenclamide treatment on beta cell function in recently diagnosed Type 2 diabetic patients.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 798-Conference paper (Other academic)
  • 2. Bakhtadze, E
    et al.
    Borg, H
    Stenström, G
    Fernlund, P
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ekbom-Schnell, A
    Bolinder, J
    Eriksson, JW
    Gudbjörnsdottir, S
    Nyström, L
    Groop, LC
    Sundkvist, G
    HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 8, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients. Subjects and methods: Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15-34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743. Results: Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003). Conclusions/ interpretation: Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes. © Springer-Verlag 2006.

  • 3.
    Bakhtadze, E
    et al.
    Lund University.
    Cervin, C
    Lund University.
    Lindholm, E
    Lund University.
    Borg, H
    Lund University.
    Nilsson, P
    Lund University.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Bolinder, J
    Karolinska University.
    Eriksson, J W
    Umeå University Hospital.
    Gudbjornsdottir, S
    Sahlgrens University Hospital.
    Nystrom, L
    Umeå University Hospital.
    Agardh, C D
    Lund University.
    Landin-Olsson, M
    Lund University Hospital.
    Sundkvist, G
    Lund University Hospital.
    C Groop , L C
    Lund University Hospital.
    Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15-34 years) but not in middle-aged (40-59 years) diabetic patients2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 12, p. 2224-2232Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients.

    In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide.

    Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p =9.4x10(-34); 45% vs 18%, p= 1.4x10(-16)), PTPN22 CT/TT (34% vs 26%, p=0.0023; 31% vs 23%, p=0.034), INS VNTR class I/I (69% vs 53%, p=1.3x10(-8); 69% vs 51%, p=8.5x10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p=4.3x10(-6); 73% vs 60%, p=0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p=0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%).

    Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.

  • 4.
    Beam, Craig A.
    et al.
    Western Michigan University, MI 49008 USA.
    MacCallum, Colleen
    Western Michigan University, MI 49008 USA.
    Herold, Kevan C.
    Yale University, CT USA; Yale University, CT USA.
    Wherrett, Diane K.
    Hospital Sick Children, Canada; University of Toronto, Canada.
    Palmer, Jerry
    University of Washington, WA 98195 USA; VA Puget Sound Health Care Syst, WA USA.
    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.
    GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 1, p. 43-49Article in journal (Refereed)
    Abstract [en]

    GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). We estimate that there is a 98% probability that 20 mu g GAD with alum administered twice yields a positive biological effect. The effect is probably a 15-20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between -0.250 and -0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of -0.294 pmol/ml at 1 year for untreated newly diagnosed patients. The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes.

  • 5. Borg, H
    et al.
    Björk, E
    Bolinder, J
    Eriksson, JW
    Nyström, L
    Jeppsson, J-O
    Sundkvist, G
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Evaluation of the new ADA and WHO criteria for classification of diabetes mellitus in young adult people (15-34 yrs) in the Diabetes Incidence Study in Sweden (DISS)2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, no 2, p. 173-181Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis. We aimed to evaluate how an aetiology-based classification, as recommended in the ADA and WHO guidelines for classification of diabetes mellitus, matches clinical judgement in the Diabetes Incidence Study in Sweden (DISS), a study covering incident cases of diabetic patients aged 15 to 34 years. Methods. During a 1-year period (1998), blood samples were taken at diagnosis and 4 months (median) thereafter. Patients were classified according to clinical judgement by the reporting physicians and assessments of islet antibodies (ICA, GADA, and IA-2A) and plasma C-peptide. Results. In 1998, 422 patients were registered in DISS. Among the 313 patients participating in the follow-up, most with clinical Type 1 diabetes (185/218, 85%, 95% CI 79-89%) were islet antibody positive (ab+) at diagnosis. In addition, 14 out of 58 (24%, 14-37%) with clinical Type 2 diabetes and 21 out of 37 (57%, 40-73%) with unclassifiable diabetes were antibody positive at diagnosis. Further to this, 4 out of 33 (12%, 3-28%) were antibody negative with clinical Type 1 diabetes and 4 out of 44 (9%, 3-22%) with Type 2 had converted to antibody positive at follow-up. Among those who were constantly antibody negative, 10 out of 29 (34%, 18-54%) with clinical Type 1 and 1 out of 16 (6%, 0-30%) with unclassifiable diabetes had fasting plasma C-peptide concentrations below the normal range (<0.25 nmol/l) at follow-up. Conclusion/interpretation. Most young adults with clinical Type 1 diabetes (199/218, 91%) had objective Type 1 (ab+ at diagnosis/follow-up and/or low fasting plasma C-peptide concentrations at follow-up), as did one third (18/58, 31%) with clinical Type 2 diabetes and more than half (22/37, 59%) with unclassifiable diabetes. About 10% of those who were antibody negative converted to antibody positive. Our study underlines that a classification considering aetiology is superior to clinical judgement.

  • 6. Chisalita, SI
    et al.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    IGF-I receptors are more expressed than insulin receptors in human coronary artery endothelial cells.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 1191-Conference paper (Other academic)
  • 7.
    Chisalita, Simona I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 10, p. 2155-2161Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Hyperinsulinaemia and insulin resistance, as well as low IGF-I, have been implicated in the pathogenesis of cardiovascular disease. Little is known about direct effects of IGF-I and insulin on human coronary artery smooth muscle cells (HCASMCs). Our aim was to characterise the expression and function of IGF-I receptor (IGF-IR) and insulin receptor (IR) in HCASMCs. Materials and methods: Cultured HCASMCs were used. mRNA expression was measured by quantitative real-time RT-PCR analysis. Receptor proteins, phosphorylation of β-subunits and the presence of hybrid IR/IGF-IR were analysed by immunoprecipitation and western blotting. DNA synthesis and glucose metabolism were assessed using [3H]thymidine incorporation and D-[U-14C]glucose accumulation respectively. Results: The mRNA expression of IGF-IR was approximately eight-fold higher than that of IR in HCASMCs. The presence of IGF-IR and IR could be demonstrated by immunoprecipitation and western blot analysis. Phosphorylation of the IGF-IR β-subunit was obtained by IGF-I at 10−10–10−8 mol/l and insulin at 10−8 mol/l. Insulin and IGF-I at 10−10–10−9 mol/l phosphorylated the IR β-subunit. When immunoprecipitated with monoclonal anti-IR α-subunit or IGF-IR α-subunit antibodies, we found bands in slightly different positions, suggesting the presence of hybrid IR/IGF-IR. IGF-I at 10−9–10−8 mol/l significantly stimulated [3H]thymidine incorporation and at a concentration of 10−9–10−7 mol/l also D-[U-14C]glucose accumulation in HCASMCs. Insulin at 10−9–10−7 mol/l had no effect on DNA synthesis, but increased glucose accumulation at 10−7 mol/l. Conclusions/interpretation: Our study provides experimental evidence that IGF-IR and possibly hybrid IR/IGF-IR play a role in HCASMCs.

  • 8. Danne, Thomas
    et al.
    Battelino, T
    Jarosz-Chobot, P
    Kordonouri, O
    Pankowska, E
    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.
    al, et
    Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: Experience of the PedPump Study in 17 countries2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 9, p. 1594-1601Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome. Methods: Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA 1c was measured centrally. Results: A total of 1,041 patients (age: 11.8±4.2 years, diabetes duration: 6.0±3.6 years, average CSII duration: 2.0±1.3 years, HbA1c: 8.0±1.3% [means±SD]) participated. Glycaemic control was better in preschool (n=142, 7.5±0.9%) and pre-adolescent (6-11 years, n=321, 7.7±1.0%) children than in adolescent patients (12-18 years, n=578, 8.3±1.4%). There was a significant negative correlation between HbA1c and daily bolus number, but not between HbA1c and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA1c level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively. Conclusions/ interpretation: This large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA1c. © 2008 Springer-Verlag.

  • 9.
    Franck, Niclas
    et al.
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Stenkula, Karin G.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik H.
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 8, p. 1716-1722Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Several studies have suggested that large fat cells are less responsive to insulin than small fat cells. However, in these studies, large fat cells from obese individuals were compared with smaller fat cells from leaner participants, in effect making it impossible to draw conclusions about whether there is a causal relationship between fat cell size and insulin sensitivity. We hypothesised that small fat cells might be more insulin-responsive than large adipocytes when obtained from the same individual.

    Materials and methods: We developed a method of sorting isolated primary human fat cells by using nylon filters of two different pore sizes. The cells were stained to visualise DNA, which allowed discrimination from artefacts such as lipid droplets. The sorted cells were left to recover overnight, since we had previously demonstrated that this is necessary for correct assessment of insulin response.

    Results: We found similar amounts of the insulin receptor (IR), IRS-1 and GLUT4 when we compared small and large adipocytes from the same volunteer by immunoblotting experiments using the same total cell volume from both cell populations. Activation of IR, IRS-1 and Akt1 (also known as protein kinase B) by insulin was similar in the two cell populations. However, immunofluorescence confocal microscopy of plasma membrane sheets did not reveal any increase in the amount of GLUT4 in the plasma membrane following insulin stimulation in the large fat cells, whereas we saw a twofold increase in the amount of GLUT4 in the small fat cells.

    Conclusions/interpretation: Our results support a causal relationship between the accumulation of large fat cells in obese individuals and reduced insulin responsiveness.

  • 10.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 10, p. 2435-2442Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown. Methods The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes. Results Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals. Conclusions/interpretation Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

  • 11.
    Guldbrand, Hans
    et al.
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences.
    Dizdar, B.
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences.
    Bunjaku, B.
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Primary Health Care in Motala.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    In type 2 diabetes, randomisation to advice to follow a low-carbohydrate diet transiently improves glycaemic control compared with advice to follow a low-fat diet producing a similar weight loss2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 8, p. 2118-2127Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The study aimed to compare the effects of a 2 year intervention with a low-fat diet (LFD) or a low-carbohydrate diet (LCD), based on four group meetings to achieve compliance. METHODS: This was a prospective randomised parallel trial involving 61 adults with type 2 diabetes consecutively recruited in primary care and randomised by drawing ballots. Patients that did not speak Swedish could not be recruited. The primary outcomes in this non-blinded study were weight and HbA(1c). Patients on the LFD aimed for 55-60 energy per cent (E%) and those on LCD for 20 E% from carbohydrate. RESULTS: The mean BMI and HbA(1c) of the participants were 32.7 ± 5.4 kg/m(2) and 57.0 ± 9.2 mmol/mol, respectively. No patients were lost to follow-up. Weight loss did not differ between groups and was maximal at 6 months: LFD -3.99 ± 4.1 kg (n = 31); LCD -4.31 ± 3.6 kg (n = 30); p < 0.001 within groups. At 24 months, patients on the LFD had lost -2.97 ± 4.9 kg and those on LCD -2.34 ± 5.1 kg compared with baseline (p = 0.002 and p = 0.020 within groups, respectively). HbA(1c) fell in the LCD group only (LCD at 6 months -4.8 ± 8.3 mmol/mol, p = 0.004, at 12 months -2.2 ± 7.7 mmol/mol, p = 0.12; LFD at 6 months -0.9 ± 8.8 mmol/mol, p = 0.56). At 6 months, HDL-cholesterol had increased with the LCD (from 1.13 ± 0.33 mmol/l to 1.25 ± 0.47 mmol/l, p = 0.018) while LDL-cholesterol did not differ between groups. Insulin doses were reduced in the LCD group (0 months, LCD 42 ± 65 E, LFD 39 ± 51 E; 6 months, LCD 30 ± 47 E, LFD 38 ± 48 E; p = 0.046 for between-group change). CONCLUSIONS/INTERPRETATION: Weight changes did not differ between the diet groups, while insulin doses were reduced significantly more with the LCD at 6 months, when compliance was good. Thus, aiming for 20% of energy intake from carbohydrates is safe with respect to cardiovascular risk compared with the traditional LFD and this approach could constitute a treatment alternative. TRIAL REGISTRATION: ClinicalTrials.gov NCT01005498 FUNDING: University Hospital of Linköping Research Funds, Linköping University, the County Council of Östergötland, and the Diabetes Research Centre of Linköping University.

  • 12.
    Heintz, Emelie
    et al.
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Wiréhn, Ann-Britt
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences.
    Peebo Bourghardt, Beatrice
    Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Rosenqvist, U
    Motala Hospital, Sweden.
    Levin, Lars-Åke
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Prevalence and healthcare costs of diabetic retinopathy: a population-based register study in Sweden2010In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, no 10, p. 2147-2154Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    The aim of the present study was to estimate the prevalence and healthcare costs of diabetic retinopathy (DR).

    Methods

    This population-based study included all residents (n = 251,386) in the catchment area of the eye clinic of Linköping University Hospital, Sweden. Among patients with diabetes (n  = 12,026), those with and without DR were identified through register data from both the Care Data Warehouse in Östergötland, an administrative healthcare register, and the Swedish National Diabetes Register. Healthcare cost data were elicited by record linkage of these two registers to data for the year 2008 in the Cost Per Patient Database developed by Östergötland County Council.

    Results

    The prevalence of any DR was 41.8% (95% CI 38.9–44.6) for patients with type 1 diabetes and 27.9% (27.1–28.7) for patients with type 2 diabetes. Sight-threatening DR was present in 12.1% (10.2–14.0) and 5.0% (4.6–5.4) of the type 1 and type 2 diabetes populations respectively. The annual average healthcare cost of any DR was €72 (€53–91). Stratified into background retinopathy, proliferative DR, maculopathy, and the last two conditions combined, the costs were €26 (€10–42), €257 (€155–359), €216 (€113–318) and €433 (€232–635) respectively. The annual cost for DR was €106 000 per 100,000 inhabitants.

    Conclusions

    This study presents new information on the prevalence and costs of DR. Approximately one-third of patients with diabetes have some form of DR. Average healthcare costs increase considerably with the severity of DR, which suggests that preventing progression of DR may lower healthcare costs.

  • 13. Holdstock, C
    et al.
    Ludvigsson, Johnny
    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.
    Karlsson, FA
    Abnormal ghrelin secretion in new onset childhood Type 1 diabetes [8]2004In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 47, no 1, p. 150-151Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 14.
    Holmberg, Hanna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Fälth-Magnusson, Karin
    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.
    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.
    Induction of diabetes-related autoantibodies below cut-off for positivity in young non-diabetic children.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 317-Conference paper (Other academic)
  • 15.
    Hyllienmark, Lars
    et al.
    Avd f Klin neurofysiologi Karolinska sjukhuset, Stockholm.
    Maltez, J
    Avd f Klin neurofysiologi Karolinska sjukhuset, Stockholm.
    Dandenell, AnnaKarin
    Barnkliniken US.
    Ludvigsson, Johnny
    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, Department of Paediatrics in Linköping.
    Brismar, Tom
    Avd f Klin Neurofysiologi Karolinska sjukhuset, Stockholm.
    EEG abnormalities with and without relation to severe hypoglycaemia in adolescents with type 1 diabetes2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 3, p. 412-419Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The aim of the present study was to identify whether adolescents with type 1 diabetes receiving modern multiple insulin injection therapy (MIT) have abnormal EEGs, and to elucidate possible correlations with a history of severe hypoglycaemia, poor metabolic control and nerve conduction defects. Methods: We investigated 35 patients (age 14-19 years) with disease duration 7.6±4.6 years, and 45 healthy control subjects. EEG spectral components were obtained from 15-min recordings in resting, awake subjects. Nerve conduction was measured bilaterally in motor and sensory fibres in the median, peroneal and sural nerves. Results: The EEGs of patients showed an increase in slow activity (delta and theta) and a reduction in alpha peak frequency, both of which were most pronounced in the frontal regions (p<0.001). They also showed a decrease in fast activity, which was most pronounced bilaterally in the posterior temporal regions (alpha p<0.001, beta p<0.01, gamma p<0.001). A history of severe hypoglycaemia was correlated with a global increase in theta activity (p<0.01-0.05). Poor metabolic control, measured as acute and long-term HbA1c levels, was correlated with an increase in delta activity and a decrease in alpha peak frequency. The decrease in fast activity in the temporal regions was a separate type of abnormality because it had a different distribution, and was not correlated with the increase in delta/theta power, poor metabolic control or with hypoglycaemia. Conclusions/interpretation: Recurrent severe hypoglycaemia and poor metabolic control are risk factors for EEG abnormalities in adolescents with type 1 diabetes receiving MIT treatment. In addition, we found pronounced abnormalities in the temporal regions that were not related to these risk factors. © Springer-Verlag 2005.

  • 16.
    Jonsdottir, B
    et al.
    Lund University, Sweden .
    Andersson, C
    Lund University, Sweden .
    Carlsson, A
    Lund University, Sweden .
    Delli, A
    Lund University, Sweden .
    Forsander, G
    Karolinska Institute, Sweden .
    Ludvigsson, Johnny
    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.
    Marcus, C
    Karolinska Institute, Sweden .
    Samuelsson, Ulf
    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.
    Ortqvist, E
    Karolinska Institute, Sweden .
    Lernmark, A
    Lund University, Sweden .
    Ivarsson, S-A
    Lund University, Sweden .
    Elding Larsson, H
    Lund University, Sweden .
    Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 8, p. 1735-1742Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. less thanbrgreater than less thanbrgreater thanBlood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4). less thanbrgreater than less thanbrgreater thanAt type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p andlt; 0.0001). GADA was positively associated with TPOAb (p andlt; 0.001) and with TGAb (p andlt; 0.001). In addition, ZnT8A was associated with both TPOAb (p = 0.039) and TGAb (p = 0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p (c)) = 0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p (c) = 0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. less thanbrgreater than less thanbrgreater thanGADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.

  • 17.
    Karlsson, Maria G. E.
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Garcia, Jorge
    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.
    Cows' milk proteins cause similar Th1- and Th2-like immune response in diabetic and healthy children2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 9, p. 1140-1147Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis:   Cows' milk proteins have been proposed to play a part in the pathogenesis of Type I (insulin-dependent) diabetes mellitus but both epidemiological and immunological studies have given conflicting results. Thus we aimed to study the immunological response to cows' milk proteins among diabetic and healthy children, focusing on the balance of Th1- and Th2-like lymphocytes.

    Methods:   Peripheral blood mononuclear cells from 30 Type I diabetic children (4 to 18 years old) were examined and compared with peripheral blood mononuclear cells from 18 healthy age-matched control children (7 to 15 years old). Expression of IFN-γ and IL-4 mRNA were detected by realtime RT-PCR and as protein by ELISA after stimulation with BSA, the ABBOS-peptide (a. a. 152–169) and β-lactoglobulin (βLG) from cows' milk and ovalbumin from hens' egg. Phytohaemagglutinin and keyhole limpet haemocyanin were used as positive and negative controls, respectively.

    Results:   Bovine serum albumin caused a weak Th2-like response in Type I diabetic children, whereas BSA antibodies decreased with age only among healthy children. Otherwise, cows' milk proteins (BSA, ABBOS and βLG) caused increased expression for IFN-γ and IL-4 mRNA in diabetic and healthy children. βLG caused the strongest immunological response, which decreased with age only among diabetic children. However, ovalbumin from egg caused a similar activation of the immune system and the immune response was similar in both diabetic and healthy children.

    Conclusion/interpretation:   Proteins from cows' milk caused an equal Th1- and Th2-like immune response in diabetic and healthy children. Thus, our results do not support the hypothesis that cows' milk antigens are important for the immune process associated with Type I diabetes.

  • 18.
    Karlsson, Maria G. E.
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Sederholm Lawesson, S.
    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.
    Th1-like dominance in high-risk first-degree relatives of Type I diabetic patients2000In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 43, no 6, p. 742-749Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis. The humoral part of the immune system, including autoantibodies, is known to predict manifest Type I (insulin-dependent) diabetes mellitus in first-degree relatives but the cell-mediated immune process preceding the manifest disease still is not known. The aim of this investigation was to estimate the immunological balance of Th-like lymphocytes (Th1/Th2) in high-risk first-degree relatives of Type I diabetic children.

    Methods. Peripheral blood mononuclear cells (PBMC) from 21 healthy high-risk first-degree relatives (ICA ≥ 20) were examined and compared with the response seen in PBMC from children with newly diagnosed Type I diabetes and healthy control subjects of similar age, sex and HLA-type. Expression of interleukin-4 (IL-4) and interferon-γ (IFN-γ) mRNA were determined by RT-PCR and as protein by ELISPOT after stimulation with specific epitopes of GAD65 (a. a. 247–279, 509–528, 524–543), bovine serum albumin, the ABBOS peptide (a. a. 152–169) and insulin.

    Results. High-risk relatives had a high ratio of IFN-γ:IL-4 compared with both diabetic children (p = 0.0005) and healthy control subjects (p = 0.004). Production of IFN-γ seen in high-risk relatives was negatively correlated to production of GADA (r = –0.44, p = 0.05). The high concentration of IFN-γ from high-risk relatives, decreased after stimulation with peptides of GAD65, the ABBOS peptide, BSA and insulin. Increased secretion of IL-4 was observed after stimulation with two peptides of GAD65 (a. a. 509–528 and 524–543), the ABBOS peptide and insulin.

    Conclusion/interpretation. Overwhelming production of IFN-γ seen in peripheral blood mononuclear cells from high-risk first-degree relatives of children with Type I diabetes suggests a Th1-like immune deviation in the prediabetic phase.

  • 19. Knip, M
    et al.
    Douek, IF
    Moore, WPT
    Gillmore, HA
    McLean, AEM
    Bingley, PJ
    Gale, EAM
    Ludvigsson, Johnny
    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.
    Safety of high-dose nicotinamide: a review2000In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 43, p. 1337-1345Article in journal (Refereed)
  • 20.
    Krogvold, Lars
    et al.
    Oslo University Hospital HF, Norway .
    Edwin, Bjorn
    Oslo University Hospital, Norway .
    Buanes, Trond
    Oslo University Hospital, Norway .
    Ludvigsson, Johnny
    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.
    Korsgren, Olle
    Uppsala University, Sweden .
    Hyöty, Heikki
    University of Tampere, Finland .
    Frisk, Gun
    Uppsala University, Sweden .
    Hanssen, Kristian F.
    Oslo University Hospital, Norway .
    Dahl-Jörgensen, Knut
    Oslo University Hospital HF, Norway .
    Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 4, p. 841-843Article in journal (Refereed)
    Abstract [en]

    n/a

  • 21.
    Lindell, Nina
    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. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Carlsson, Annelie
    Lund University, Sweden.
    Josefsson, Ann
    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 Gynaecology and Obstetrics in Linköping.
    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, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Maternal obesity as a risk factor for early childhood type 1 diabetes: a nationwide, prospective, population-based case-control study2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 1, p. 130-137Article in journal (Refereed)
    Abstract [en]

    Genetic and environmental factors are believed to cause type 1 diabetes. The aim of this study was to investigate the influence of maternal BMI and gestational weight gain on the subsequent risk of childhood type 1 diabetes. Children in the Swedish National Quality Register for Diabetes in Children were matched with control children from the Swedish Medical Birth Register. Children were included whose mothers had data available on BMI in early pregnancy and gestational weight gain, giving a total of 16,179 individuals: 3231 children with type 1 diabetes and 12,948 control children. Mothers of children with type 1 diabetes were more likely to be obese (9% [n = 292/3231] vs 7.7% [n = 991/12,948]; p = 0.02) and/or have diabetes themselves (2.8% [n = 90/3231] vs 0.8% [n = 108/12,948]; p amp;lt; 0.001) compared with mothers of control children. Gestational weight gain did not differ significantly between the two groups of mothers. In mothers without diabetes, maternal obesity was a significant risk factor for type 1 diabetes in the offspring (p = 0.04). A child had an increased risk of developing type 1 diabetes if the mother had been obese in early pregnancy (crude OR 1.20; 95% CI 1.05, 1.38; adjusted OR 1.18; 95% CI 1.02, 1.36). Among children with type 1 diabetes (n = 3231) there was a difference (p amp;lt; 0.001) in age at onset in relation to the mothers BMI. Among children in the oldest age group (15-19 years), there were more mothers who had been underweight during pregnancy, while in the youngest age group (0-4 years) the pattern was reversed. Maternal obesity, in the absence of maternal diabetes, is a risk factor for type 1 diabetes in the offspring, and influences the age of onset of type 1 diabetes. This emphasises the importance of a normal maternal BMI to potentially decrease the incidence of type 1 diabetes.

  • 22. Littorin, B
    et al.
    Blom, P
    Schölin, A
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Blohmé, G
    Bolinder, J
    Ekbom-Schnell, A
    Eriksson, JW
    Gudbjörnsdottir, S
    Nyström, L
    Östman, J
    Sundkvist, G
    Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: Results from the nationwide Diabetes Incidence Study in Sweden (DISS)2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 12, p. 2847-2852Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Low plasma vitamin D concentrations may promote the development of type 1 diabetes. To test this hypothesis, we measured plasma 25-hydroxyvitamin D (25OHD) in young adults with type 1 diabetes. Methods: The nationwide Diabetes Incidence Study in Sweden (DISS) covers 15- to 34-year-old people with newly diagnosed diabetes. Blood samples at diagnosis were collected during the 2-year period 1987/1988. Patients with islet antibodies (islet cell antibodies, GAD antibodies or tyrosine phosphatase-like protein antibodies) were defined as having autoimmune type 1 diabetes. Plasma 25OHD was measured in samples taken from 459 patients at the time of diagnosis, and in 138 of these subjects 8 years later. The results were compared with age- and sex-matched control subjects (n=208). Results: At diagnosis, plasma 25OHD levels were significantly lower in patients with type 1 diabetes than in control subjects (82.5±1.3 vs 96.7±2.0 nmol/l, p<0.0001). Eight years later, plasma 25OHD had decreased in patients (81.5±2.6 nmol/l, p=0.04). Plasma 25OHD levels were significantly lower in diabetic men than in diabetic women at diagnosis (77.9±1.4 vs 90.1±2.4 nmol/l, p<0.0001) and at follow-up (77.1±2.8 nmol/l vs 87.2±4.5 nmol/l, p=0.048). Conclusions/interpretation: The plasma 25OHD level was lower at diagnosis of autoimmune type 1 diabetes than in control subjects, and may have a role in the development of type 1 diabetes. Plasma 25OHD levels were lower in men than in women with type 1 diabetes. This difference may be relevant to the high incidence of type 1 diabetes among young adult men. © 2006 Springer-Verlag.

  • 23.
    Long, Anna E.
    et al.
    Univ Bristol, England.
    Wilson, Isabel V.
    Univ Bristol, England.
    Becker, Dorothy J.
    Univ Pittsburgh, PA 15260 USA.
    Libman, Ingrid M.
    Univ Pittsburgh, PA 15260 USA.
    Arena, Vincent C.
    Univ Pittsburgh, PA 15260 USA.
    Wong, F. Susan
    Cardiff Univ, Wales.
    Steck, Andrea K.
    Univ Colorado, CO USA.
    Rewers, Marian J.
    Univ Colorado, CO USA.
    Yu, Liping
    Univ Colorado, CO USA.
    Achenbach, Peter
    Tech Univ Munich, Germany; Tech Univ Munich, Germany.
    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.
    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.
    Williams, Alistair J. K.
    Univ Bristol, England.
    Gillespie, Kathleen M.
    Univ Bristol, England.
    Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 6, p. 1484-1490Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of slow progressors (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Methods Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Barts Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed amp;lt; 5 years old from BOX) using the chi(2) test. Results In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. Conclusion No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.

  • 24.
    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.
    Adequate doses of autoantigen administered using the appropriate route may create tolerance and stop autoimmunity2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 1, p. 175-176Article in journal (Other academic)
  • 25.
    Ludvigsson, Johnny
    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.
    Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 339-346Article in journal (Refereed)
  • 26.
    Ma, Z
    et al.
    Linkoping Univ Hosp, Div Mol & Immunol Pathol, S-58185 Linkoping, Sweden Linkoping Univ Hosp, Div Cell Biol, S-58185 Linkoping, Sweden.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Effects of free fatty acids (FFAs) on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. 440-Conference paper (Other academic)
  • 27.
    Ma, Zhi
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Li, Z.-C.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Engström, U.
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Westermark, P.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis1997In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 40, no 7, p. 793-801Article in journal (Refereed)
    Abstract [en]

    We have developed a mouse monoclonal antibody against rat/mouse islet amyloid polypeptide (IAPP). The antibody recognises an epitope in the N-terminal part of the molecule, which is conserved between different species. The antibody immunohistochemically labelled beta cells in normal islets of most different mammalian species including man and in one avian species. Previous immunohistochemical studies of human pancreatic tissue from individuals with non-insulin-dependent diabetes mellitus (NIDDM) have revealed a paradoxical and unexplained lack of IAPP immunoreactivity in beta cells close to amyloid in spite of the presence of IAPP mRNA. In contrast to these findings we show that the newly developed monoclonal IAPP antibody strongly labels such beta cells while islet amyloid deposits which are labelled by polyclonal antisera do not bind the monoclonal antibody. These findings with the polyclonal antisera and the monoclonal antibody indicate that IAPP undergoes one or several structural changes during the amyloidogenesis. Knowledge of these structural changes that may include abnormal folding or chemical modification of IAPP is probably important for the understanding of the amyloidogenesis and the pathogenesis of the islet lesion in NIDDM.

  • 28.
    Mollazadegan, Kaziwe
    et al.
    Karolinska Institutet, Stockholm, Sweden; St Erik Eye Hospital, Stockholm, Sweden.
    Fored, Michael
    Karolinska Institutet, Stockholm, Sweden.
    Lundberg, Sigrid
    Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Johnny
    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.
    Ekbom, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott M.
    Karolinska Institutet, Stockholm, Sweden; Örebro University Hospital, Sweden; University of Örebro, Sweden; UCL, England .
    Ludvigsson, Jonas F.
    Karolinska Institutet, Stockholm, Sweden; Örebro University Hospital, Sweden.
    Risk of renal disease in patients with both type 1 diabetes and coeliac disease2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 7, p. 1339-1345Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Our aim was to study the risk of renal disease in patients with type 1 diabetes (T1D) and coexisting coeliac disease (CD).

    METHODS:

    Individuals with T1D were defined as having a diagnosis of diabetes recorded at ≤30 years of age in the Swedish Patient Register between 1964 and 2009. Individuals with CD were identified through biopsy reports with villous atrophy (Marsh stage 3) from 28 pathology departments in Sweden between 1969 and 2008. We identified 954 patients with both T1D and CD. For each patient with T1D + CD, we selected five age- and sex-matched reference individuals with T1D only (n = 4,579). Cox regression was used to estimate the following risks: (1) chronic renal disease and (2) end-stage renal disease in patients with CD + T1D compared with T1D patients only.

    RESULTS:

    Forty-one (4.3%) patients with CD + T1D and 143 (3.1%) patients with T1D only developed chronic renal disease. This corresponded to an HR of 1.43 for chronic renal disease (95% CI 0.94, 2.17) in patients with CD + T1D compared with T1D only. In addition, for end-stage renal disease there was a positive (albeit statistically non-significant) HR of 2.54 (95% CI 0.45, 14.2). For chronic renal disease, the excess risk was more pronounced after >10 years of CD (HR 2.03, 95% CI 1.08, 3.79). Risk estimates were similar when we restricted our cohort to the following T1D patients: (1) those who had an inpatient diagnosis of T1D; (2) those who had never received oral glucose-lowering medication; and (3) those who had not received their first diabetes diagnosis during pregnancy.

    CONCLUSIONS/INTERPRETATION:

    Overall this study found no excess risk of chronic renal disease in patients with T1D and CD. However, in a subanalysis we noted a positive association between longstanding CD and chronic renal disease in T1D.

  • 29.
    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.
    Bojestig, M
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    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.
    Declining incidence of severe retinopathy in a population of Type 1 diabetes2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, p. 1095-Conference paper (Other academic)
  • 30.
    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.
    Bojestig, M
    Linkoping Univ Hosp, Div Internal Med, S-58185 Linkoping, Sweden Linkoping Univ Hosp, Div Paediat, S-58185 Linkoping, Sweden.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    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.
    Persistent decrease in nephropathy in Type 1 diabetes2000In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 43, p. 971-Conference paper (Other academic)
  • 31.
    Nowak, Christoph
    et al.
    Karolinska Inst, Sweden.
    Carlsson, Axel C.
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Ödeshög.
    Nyström, Fredrik
    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.
    Alam, Moudud
    Dalarna Univ, Sweden.
    Feldreich, Tobias
    Dalarna Univ, Sweden.
    Sundstrom, Johan
    Uppsala Univ, Sweden.
    Carrero, Juan-Jesus
    Karolinska Inst, Sweden.
    Leppert, Jerzy
    Uppsala Univ, Sweden.
    Hedberg, Par
    Uppsala Univ, Sweden.
    Henriksen, Egil
    Uppsala Univ, Sweden.
    Cordeiro, Antonio C.
    Dante Pazzanese Inst Cardiol, Brazil.
    Giedraitis, Vilmantas
    Uppsala Univ, Sweden.
    Lind, Lars
    Uppsala Univ, Sweden.
    Ingelsson, Erik
    Stanford Univ, CA 94305 USA.
    Fall, Tove
    Uppsala Univ, Sweden.
    Arnlov, Johan
    Karolinska Inst, Sweden; Dalarna Univ, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 8, p. 1748-1757Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. Methods We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Results Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (+/- SD) of 6.4 +/- 2.3 years. We replicated associations (amp;lt; 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. Conclusions/interpretation We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.

  • 32.
    Nygren, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Koch, Felix-Sebastian
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Linköping University, Faculty of Health Sciences.
    Frostell, Anneli
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Experience of a serious life event increases the risk for childhood type 1 diabetes: the ABIS population-based prospective cohort study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 6, p. 1188-1197Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis The aim of this study was to prospectively investigate whether psychological stress during childhood may be a risk factor for manifest type 1 diabetes. Methods The All Babies In Southeast Sweden (ABIS) study invited all families with babies born between 1 October 1997 and 30 September 1999 in southeast Sweden to participate. Our study subsample includes 10,495 participants in at least one of the data collections at 2-3, 5-6, 8 and 10-13 years of age not yet diagnosed with type 1 diabetes at inclusion; 58 children were subsequently diagnosed. Age at diagnosis was obtained from the national register SweDiabKids in 2012. Family psychological stress was measured via questionnaires given to the parents assessing serious life events, parenting stress, parental worries and the parents social support. Results Childhood experience of a serious life event was associated with a higher risk of future diagnosis of type 1 diabetes (HR 3.0 [95% CI 1.6, 5.6], p = 0.001) after adjusting for heredity of type 1 diabetes and age at entry into the study. The result was still valid when controlling for heredity of type 2 diabetes, size for gestational age, the parents education level and whether the mother worked at least 50% of full time before the childs birth (HR 2.8 [95% CI 1.5, 5.4], p = 0.002), and also when childhood BMI was added to the model (HR 5.0 [95% CI 2.3, 10.7], p less than 0.001). Conclusions/interpretation This first prospective study concluded that experience of a serious life event in childhood may be a risk factor for manifest type 1 diabetes.

  • 33. Nystrom, FH
    et al.
    Strålfors, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Stenkula, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Transfection of human fatcells by electroporation2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. 592-Conference paper (Other academic)
  • 34. Olsen, H
    et al.
    Länne, Toste
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Vascular surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Reduced capillary hydraulic conductivity in skeletal muscle and skin in Type 1 diabetes: a possible cause for reduced transcapillary fluid absorption during hypovolaemia.2000In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 43, p. 1178-1184Article in journal (Refereed)
  • 35. Osman, Ayman A. M.
    et al.
    Dahlin, Lars B.
    Lund University, Sweden; Skåne University Hospital Malmö, Sweden.
    Thomsen, Niels O. B.
    Lund University, Sweden; Skåne University Hospital Malmö, Sweden.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 3, p. 625-632Article in journal (Refereed)
    Abstract [en]

    We addressed the question of whether the autophagy pathway occurs in human peripheral nerves and whether this pathway is associated with peripheral neuropathy in diabetes mellitus. By using electron microscopy, we evaluated the presence of autophagy-related structures and neuropathy in the posterior interosseous nerve of patients who had undergone carpal tunnel release and had type 1 or type 2 diabetes mellitus, and in patients with no diabetes (controls). Autophagy-related ultrastructures were observed in the samples taken from all patients of the three groups. The number of autophagy-associated structures was significantly higher (p less than 0.05) in the nerves of patients with type 1 than type 2 diabetes. Qualitative and quantitative evaluations of fascicle area, diameter of myelinated and unmyelinated nerve fibres, the density of myelinated and unmyelinated fibres and the g-ratio of myelinated fibres were performed. We found degeneration and regeneration of a few myelinated axons in controls, and a well-developed neuropathy with the loss of large myelinated axons and the presence of many small ones in patients with diabetes. The pathology in type 1 diabetes was more extensive than in type 2 diabetes. The results of this study show that the human peripheral nerves have access to the autophagy machinery, and this pathway may be regulated differently in type 1 and type 2 diabetes; insulin, presence of extensive neuropathy, and/or other factors such as duration of diabetes and HbA(1c) level may underlie this differential regulation.

  • 36.
    Paulsson, Johan
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Andersson, A.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Westermark, P.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 6, p. 1237-1246Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Islet amyloid is a frequent finding in the islets of Langerhans of individuals with type 2 diabetes. The main amyloid constituent is the beta cell-derived polypeptide hormone islet amyloid polypeptide (IAPP). In general, amyloid refers to an extracellular deposit of a congophilic material, but intracellular amyloid is seen in some beta cells of transgenic mice expressing the gene for human IAPP and in human islets transplanted into nude mice. The aim of this study was to immunohistochemically characterise the intracellular amyloid. Methods: Antisera against the N- and C-terminal processing sites of proIAPP (which were therefore specific for proIAPP), the C-terminal flanking peptide and mature IAPP were used for immunoelectron microscopy. Results: Fibrillar aggregates were seen in the halo region of the secretory granules in some beta cells in human IAPP transgenic mice. These aggregates were labelled with proIAPP-specific antisera. Also, proIAPP reactivity was more widespread in the intracellular amyloid-like aggregates in beta cells of transgenic mice than in human islet transplants, in which the intracellular amyloid-like deposits were larger, but the proIAPP labelling was restricted to small spots within the amyloid deposits. Conclusions/ interpretation: We suggest that proIAPP forms the first amyloid fibrils and that this can occur already in the secretory granules of the beta cells. The proIAPP-derived fibrils can act as seed for further amyloid formation, now made up by IAPP. The observed difference between human islet transplants and human IAPP transgenic animals may reflect differences in stages of amyloid development. © Springer-Verlag 2006.

  • 37.
    Persson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    A lysosomotropic form of alpha-lipoic acid: a possible therapy of diabetic complications?2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. A175-A175Article in journal (Other academic)
    Abstract [en]

    n/a

  • 38.
    Persson, M. Friederich
    et al.
    Biomed Centre, Uppsala.
    Franzen, S.
    Biomed Centre, Uppsala.
    Catrina, S-B
    Karolinska Institute, Stockholm.
    Dallner, G.
    Karolinska Institute, Stockholm.
    Hansell, P.
    Biomed Centre, Uppsala.
    Brismar, K.
    Karolinska Institute, Stockholm.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 5, p. 1535-1543Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis  Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. 

    Methods  Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.

    Results  Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O2 s−1 [mg protein]−1), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 μl/min), increased proteinuria (21 ± 2 vs 14 ± 1, μg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 μm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (−1.1 ± 0.1 pmol O2 s−1 [mg protein]−1). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD).

    Conclusions/interpretation  db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

  • 39.
    Pham, M N.
    et al.
    University of Dusseldorf, Germany .
    Kolb, H
    University of Dusseldorf, Germany .
    Battelino, T
    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, P
    University of Campus BioMed, Italy .
    Zivehe, F
    University of Dusseldorf, Germany .
    Roden, M
    University of Dusseldorf, Germany .
    Mandrup-Poulsen, T
    University of Copenhagen, Denmark .
    Schloot, N C.
    University of Dusseldorf, Germany .
    Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 6, p. 1356-1363Article in journal (Refereed)
    Abstract [en]

    Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. less thanbrgreater than less thanbrgreater thanThe beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-alpha), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-beta(1-3)) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA(1c) and fasting blood glucose. less thanbrgreater than less thanbrgreater thanHigh fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-alpha were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p andlt; 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-beta(1) and TGF-beta(2) were associated with lower fasting and stimulated C-peptide levels (p andlt; 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-alpha increased (p andlt; 0.001) while those of IL-10 and TGF-beta(1) decreased (p andlt; 0.02) and IL-1RA and TGF-beta(2) remained unchanged. less thanbrgreater than less thanbrgreater thanThe association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.

  • 40. Pundziute-Lycka, A
    et al.
    Dahlquist, G
    Nystrom, L
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bjork, E
    Blohme, G
    Bolinder, J
    Eriksson, JW
    Sundkvist, G
    Ostman, J
    The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983 to 19982002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, no 6, p. 783-791Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis. To analyse the incidence of Type I (insulin-dependent) diabetes mellitus in the 0-34 years age group in Sweden 1983-1998. Methods. Incidence and cumulative incidence per 100 000 and Poisson regression analysis of age-period effects was carried out using 11 751 cases from two nation-wide prospective registers. Results. Incidence (95%-CI) was 21.4 (20.8-21.9) in men and 17.1 (16.6-17.5) in women between 0 and 34 years of age. In boys aged 0-14 and girls aged 0-12 years the incidence increased over time, but it tended to decrease at older age groups, especially in men. Average cumulative incidence at 35 years was 748 in men and 598 in women. Cumulative incidence in men was rather stable during four 4-year periods (736, 732, 762, 756), while in women it varied more (592, 542, 617, 631). In males aged 0-34 years, the incidence did not vary between the 4-year periods (p=0.63), but time changes among the 3-year age groups differed (p<0.001). In females the incidence between the periods varied (p<0.001), being lower in 1987-1990 compared to 1983-1986, but time changes in the age groups did not differ (p=0.08). For both sexes median age at diagnosis was higher in 1983-1986 than in 1995-1998 (p<0.001) (15.0 and 12.5 years in males, 11.9 and 10.4 in females, respectively). Conclusion/interpretation. During a 16-year period the incidence of Type I diabetes did not increase in the 0-34 years age group in Sweden, while median age at diagnosis decreased. A shift to younger age at diagnosis seems to explain the increasing incidence of childhood Type I diabetes.

  • 41.
    Rawshani, Araz
    et al.
    Nationella Diabetesregistret, Registercentrum VGR, Gothenburg, Sweden.
    Landin-Olsson, Mona
    Lund University, Sweden .
    Svensson, Ann-Marie
    Nationella Diabetesregistret, Registercentrum VGR, Gothenburg, Sweden.
    Nystrom, Lennarth
    Umeå University, Sweden .
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Bolinder, Jan
    Karolinska Institute, Stockholm, Sweden .
    Gudbjornsdottir, Soffia
    Nationella Diabetesregistret, Registercentrum VGR, Gothenburg, Sweden.
    The incidence of diabetes among 0-34 year olds in Sweden: new data and better methods2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 7, p. 1375-1381Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    We reassessed the validity of previously reported incidence rates for type 1 diabetes in 0-34 year olds in Sweden. We estimated new incidence rates through three nationwide registers.

    METHODS:

    We used capture-recapture methods to assess ascertainment in the Diabetes Incidence Study in Sweden (DISS) and estimated incidence rates in the 20-34 year age group for 2007-2009. We examined whether incidence rates in patients aged 34 and younger could be estimated through the Prescribed Drug Register (PDR) via a proxy for diagnosis of type 1 diabetes; men with at least one and women with at least three prescriptions for insulin were included if they had not been given oral glucose-lowering drugs. We scrutinised the proxy by comparing incidence rates in patients aged 14 and younger with the Swedish Childhood Diabetes Register (SCDR), which has 95-99% ascertainment, and by assessing diabetes type among 18-34 year olds in the National Diabetes Register (NDR).

    RESULTS:

    Incidence rates were two to three times higher than previously reported. The absolute number of cases (2007-2009, age 20-34) was 435 in the DISS, 923 in the NDR, 1,217 in the PDR, 1,431 in all three and 1,617 per the capture-recapture method. Ascertainment in the DISS was ~29% for 2007-2009. The proxy diagnosis in the PDR was highly reliable, while the capture-recapture method presumably generated an overestimate.

    CONCLUSIONS/INTERPRETATION:

    The incidence of type 1 diabetes in patients aged 34 and younger was two to three times higher than previously reported. The PDR can be used to reliably assess incidence rates in this age group.

  • 42. Rydén Ahlgren, Å
    et al.
    Åstrand, H
    Sundkvist, G
    Länne, Toste
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Increased aortic stiffness is persistent in type 1 diabetic women: A follow-up study2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 4, p. 780-783Article in journal (Other academic)
    Abstract [en]

    Aims/hypothesis: We have previously reported that women, not men, with type 1 diabetes have increased aortic stiffness. Increased arterial stiffness may explain why diabetic women have a particularly high risk of developing cardiovascular complications. We have now followed up our previously investigated patients after 7 years, with a view to evaluating whether the sex difference was persistent, and also evaluating the degree of progression with time and the relationship between stiffness versus intima media thickness of the aorta. Methods: Stiffness (β) of the abdominal aorta (echo-tracking sonography) and intima media thickness (B-mode ultrasound) were assessed in 23 women and 19 men with type 1 diabetes and compared with matched healthy individuals. Results: At follow-up, aortic stiffness was still higher (60%) (p=0.0016) in diabetic than in control women, whereas there was no similar difference (p=0.4) between diabetic and control men. No progression of stiffness had occurred over the 7 years. At follow-up, the intima media thickness was increased and the internal diameter of the aorta was decreased in diabetic men and women without any sex-related difference. Conclusions/interpretation: The increased aortic stiffness that affects type 1 diabetic patients seems to be an early event that soon reaches a plateau without any further increase. Increased aortic stiffness in type 1 diabetic women seems to be a sex-specific functional disorder unrelated to the degree of underlying atherosclerosis. © Springer-Verlag 2005.

  • 43.
    Samuelsson, Ulf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Lindell, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Akesson, Karin
    Ryhov County Hospital, Sweden; Futurum Academic Health and Care, Sweden; Jonköping University, Sweden.
    Carlsson, Annelie
    Lund University, Sweden.
    Josefsson, Ann
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Caesarean section per se does not increase the risk of offspring developing type 1 diabetes: a Swedish population-based study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, p. 2517-2524Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Some studies have revealed a relationship between Caesarean section (CS) and type 1 diabetes, while other studies have not. By using the Swedish paediatric quality register we investigated whether birth by CS is related to the risk of developing type 1 diabetes during childhood. Methods All children diagnosed with type 1 diabetes from 2000 to 2012 and included in the register (n= 9,376) were matched with four controls by year, day of birth, sex and county of birth from the Swedish Medical Birth Register. Results Overall, 13.5% of deliveries were by CS. By group, 14.7% of children who developed type 1 diabetes were delivered by CS compared with 13.3% of control children (p less than 0.001). Mothers with diabetes more often gave birth by CS than mothers without diabetes (78.8% vs 12.7%, p less than 0.001). In a logistic regression model adjusting for maternal age, maternal diabetes and BMI in early pregnancy, the OR for CS was 1.0. A child who developed type 1 diabetes and had a mother with type 1 diabetes at the time of delivery had the highest OR to have been born by CS. Children of mothers without diabetes, delivered by CS, had no increased risk of developing type 1 diabetes. Maternal diabetes was the strongest predictor of childhood diabetes (OR 3.4), especially if the mother had type 1 diabetes (OR 7.54). Conclusions/interpretation CS had no influence on the risk of type 1 diabetes during childhood or adolescence. However, maternal diabetes itself strongly increased the risk of offspring developing type 1 diabetes.

  • 44.
    Sauma, Lilian
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franck, Niclas
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Paulsson, Johan F
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kjølhede, Preben
    Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 1, p. 195-201Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The amount of visceral fat mass strongly relates to insulin resistance in humans. The transcription factor peroxisome proliferator activated receptor gamma (PPARG) is abundant in adipocytes and regulates genes of importance for insulin sensitivity. Our objective was to study PPARG activity in human visceral and subcutaneous adipocytes and to compare this with the most common model for human disease, the mouse.

    MATERIALS AND METHODS: We transfected primary human adipocytes with a plasmid encoding firefly luciferase controlled by PPARG response element (PPRE) from the acyl-CoA-oxidase gene and measured PPRE activity by emission of light. RESULTS: We found that PPRE activity was 6.6-fold higher (median) in adipocytes from subcutaneous than from omental fat from the same subjects (n = 23). The activity was also 6.2-fold higher in subcutaneous than in intra-abdominal fat cells when we used a PPARG ligand-binding domain-GAL4 fusion protein as reporter, demonstrating that the difference in PPRE activity was due to different levels of activity of the PPARG receptor in the two fat depots. Stimulation with 5 micromol/l rosiglitazone did not induce a PPRE activity in visceral adipocytes that was as high as basal levels in subcutaneous adipocytes. Interestingly, in mice of two different strains the PPRE activity was similar in visceral and subcutaneous fat cells.

    CONCLUSIONS/INTERPRETATION: We found considerably lower PPARG activity in visceral than in subcutaneous primary human adipocytes. Further studies of the molecular mechanisms behind this difference could lead to development of drugs that target the adverse effects of visceral obesity.

  • 45.
    Schlosser, M
    et al.
    Linkoping Univ, Dept Mol & Clin Med, Div Pediat, S-58183 Linkoping, Sweden.
    Wassmuth, R
    Linkoping Univ, Dept Mol & Clin Med, Div Pediat, S-58183 Linkoping, Sweden.
    Strebelow, M
    Linkoping Univ, Dept Mol & Clin Med, Div Pediat, S-58183 Linkoping, Sweden.
    Rjasanowski, I
    Linkoping Univ, Dept Mol & Clin Med, Div Pediat, S-58183 Linkoping, Sweden.
    Ziegler, M
    Linkoping Univ, Dept Mol & Clin Med, Div Pediat, S-58183 Linkoping, Sweden.
    Multiple Type 1 diabetes-associated autoantibodies in healthy schoolchildren reflect genetic predisposition for Type 1 diabetes2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. 142-Conference paper (Other academic)
  • 46.
    Scholin, AE
    et al.
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Bjorklund, L
    Borg, H
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Arnqvist, H
    Bjork, E
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Blohme, G
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Bolinder, J
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Eriksson, JW
    Nystrom, L
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Ostman, J
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Sundkvist, G
    Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden Univ Hosp, Dept Endocrinol, Malmo, Sweden DISS, Linkoping, Sweden DISS, Uppsala, Sweden DISS, Stockholm, Sweden DISS, Umea, Sweden DISS, Malmo, Sweden.
    Islet antibodies at diagnosis versus beta-cell function eight years later in young adult patients with diabetes.2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. 476-Conference paper (Other academic)
  • 47.
    Strollo, Rocky
    et al.
    University of Campus Biomed Roma, Italy.
    Vinci, Chiara
    University of Campus Biomed Roma, Italy; Queen Mary University of London, England.
    Napoli, Nicola
    University of Campus Biomed Roma, Italy; IRCCS Ist Ortoped Galeazzi, Italy.
    Pozzilli, Paolo
    University of Campus Biomed Roma, Italy; Queen Mary University of 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, Department of Paediatrics in Linköping.
    Nissim, Ahuva
    Queen Mary University of London, England.
    Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 8, p. 1467-1474Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis We have shown that autoimmunity to insulin in type 1 diabetes may result from neoepitopes induced by oxidative post-translational modifications (oxPTM). Antibodies specific to oxPTM-insulin (oxPTM-INS-Ab) are present in most newly diagnosed individuals with type 1 diabetes and are more common than autoantibodies to native insulin. In this study, we investigated whether oxPTM-INS-Ab are present before clinical onset of type 1 diabetes, and evaluated the ability of oxPTM-INS-Ab to identify children progressing to type 1 diabetes. Methods We used serum samples collected longitudinally from the All Babies in Southeast Sweden (ABIS) cohort tested for the gold standard islet autoantibodies to insulin (IAA), GAD (GADA), tyrosine phosphatase 2 (IA-2A) and zinc transporter 8 (ZnT8A). We studied 23 children who progressed to type 1 diabetes (progr-T1D) and 63 children who did not progress to type 1 diabetes (NP) after a median follow-up of 10.8 years (interquartile range 7.7-12.8). Of the latter group, 32 were positive for one or more islet autoantibodies (NP-AAB(+)). oxPTM-INS-Ab to insulinmodified by (OH)-O-center dot or HOCl were measured by our developed ELISA platform. Results Antibodies to at least one oxPTM-INS were present in 91.3% of progr-T1D children. oxPTM-INS-Ab co-existed with GADA, IA-2A, IAA or ZnT8A in 65.2%, 56.5%, 38.9% and 33.3% progr-T1D children, respectively. In addition, oxPTM-INS-Ab were present in 17.4%, 26.1%, 38.9% and 41.6% of progr-T1D children who were negative for GADA, IA-2A, IAA and ZnT8A, respectively. (OH)-O-center dot-INS-Ab were more common in progr-T1D children than in NP-AAB+ children (82.6% vs 19%; p amp;lt; 0.001) and allowed discrimination between progr-T1D and NP-AAB(+) children with 74% sensitivity and 91% specificity. None of the NP-AAB(-) children were positive for oxPTM-INS-Ab. Conclusions/interpretation oxPTM-INS-Ab are present before the clinical onset of type 1 diabetes and can identify children progressing to type 1 diabetes.

  • 48.
    Tavira Iglesias, Beatriz
    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.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Axelsson Chéramy, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    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.
    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.
    Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD(65)-induced immune response2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 7, p. 1276-1283Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis A European Phase III trial of GAD formulated with aluminiumhydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response. Methods In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD(65)-induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum. Results GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was amp;gt;= 210 days (p amp;lt; 0.05). In the group that received two doses of GAD-alum, levels of several GAD(65)-induced cytokines were higher in participants who received the H1N1 vaccination and the first GADalum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum. Conclusions/interpretation In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. amp;lt; 150 days, seemed to affect both GAD(65)-induced immune response and C-peptide preservation.

  • 49.
    Vaarala, Outi
    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.
    Klemetti, P
    Juhela, S
    Simell, O
    Hyöty, H
    Ilonen, J
    The effect of coincident enterovirus infection and cow-s milk exposure on immunization to insulin in early infancy.2002In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 45, p. 531-534Article in journal (Refereed)
  • 50.
    Vaarala, Outi
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Tossavainen, O
    Paronen, J
    Ronkainen, M
    Ilonen, J
    Knip, M
    Virtanen, SM
    Akerblom, HK
    Reduced primary immunization to insulin in infants who received cow milk formula with low insulin content.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 305-Conference paper (Other academic)
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