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  • 1.
    Adolfsson, Peter
    et al.
    Gothenburg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy,University of Gothenburg, Gothenburg, Sweden.
    Örnhagen, Hans
    Swedish Sports Diving Federation, Farsta, Sweden.
    Eriksson, Bengt M.
    Hyperbaric Medicine, Department of Anesthesiology, Karolinska University Hospital, Solna, Sweden.
    Cooper, Ken
    Medtronic Diabetes (Sensor R&D), Northridge CA, USA.
    Jendle, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden; Endocrine and Diabetes Center, Karlstad Hospital, Karlstad, Sweden.
    Continuous glucose monitoring: a study of the Enlite sensor during hypo- and hyperbaric conditions2012In: Diabetes Technology & Therapeutics, ISSN 1520-9156, E-ISSN 1557-8593, Vol. 14, no 6, p. 527-532Article in journal (Refereed)
    Abstract [en]

    Background: The performance and accuracy of the Enlite(™) (Medtronic, Inc., Northridge, CA) sensor may be affected by microbubble formation at the electrode surface during hypo- and hyperbaric conditions. The effects of acute pressure changes and of prewetting of sensors were investigated.

    Materials and Methods: On Day 1, 24 sensors were inserted on the right side of the abdomen and back in one healthy individual; 12 were prewetted with saline solution, and 12 were inserted dry. On Day 2, this procedure was repeated on the left side. All sensors were attached to an iPro continuous glucose monitoring (CGM) recorder. Hypobaric and hyperbaric tests were conducted in a pressure chamber, with each test lasting 105 min. Plasma glucose values were obtained at 5-min intervals with a HemoCue(®) (Ängelholm, Sweden) model 201 glucose analyzer for comparison with sensor glucose values.

    Results: Ninety percent of the CGM systems operated during the tests. The mean absolute relative difference was lower during hyperbaric than hypobaric conditions (6.7% vs. 14.9%, P<0.001). Sensor sensitivity was slightly decreased (P<0.05) during hypobaric but not during hyperbaric conditions. Clarke Error Grid Analysis showed that 100% of the values were found in the A+B region. No differences were found between prewetted and dry sensors.

    Conclusions: The Enlite sensor performed adequately during acute pressure changes and was more accurate during hyperbaric than hypobaric conditions. Prewetting the sensors did not improve accuracy. Further studies on type 1 diabetes subjects are needed under various pressure conditions.

  • 2.
    Agardh, Carl-David
    et al.
    Lund University, Lund, Sweden.
    Ahrén, Bo
    Lund University, Lund, Sweden.
    Hanås, Ragnar
    Jansson, Stefan
    Örebro University Hospital. Örebro University, School of Medical Sciences. Uppsala University, Uppsala, Sweden.
    Smith, Ulf
    Gothenburg University, Gothenburg, Sweden.
    Toft, Eva
    Karolinska Institutet, Stockholm, Sweden.
    Östenson, Claes-Göran
    Karolinska Institutet, Stockholm, Sweden.
    Varning för okritisk användning av överviktskirurgi vid typ 2-diabetes2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 25, p. 1208-1209Article in journal (Refereed)
    Abstract [sv]

    Överviktskirurgi diskuteras nu som ett behandlingsalternativ även för patienter med typ 2-diabetes där BMI inte överstiger nuvarande indikationsgräns 35 kg/m2. Artikelförfattarna vill varna för en sådan utveckling i avvaktan på kritisk värdering av denna typ av kirurgi.

  • 3. Albertsson-Wikland, Kerstin
    et al.
    Aronson, A. Stefan
    Gustafsson, Jan
    Hagenäs, Lars
    Ivarsson, Sten A.
    Jonsson, Björn
    Kriström, Berit
    Marcus, Claude
    Nilsson, Karl Olof
    Ritzén, E. Martin
    Tuvemo, Torsten
    Westphal, Otto
    Åman, Jan
    Örebro University, School of Health and Medical Sciences.
    Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 11, p. 4342-4350Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH).

    OBJECTIVE: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls.

    DESIGN AND SETTING: A randomized, controlled, long-term multicenter trial was conducted in Sweden.

    INTERVENTION: Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated.

    SUBJECTS: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population.

    MAIN OUTCOME MEASURES: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS.

    RESULTS: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations.

    CONCLUSION: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls. 

  • 4.
    Albertsson-Wikland, Kerstin
    et al.
    Goteborg Pediat Growth Res Ctr, Dept Pediat, Inst Clin Sci, Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Kriström, Berit
    Dept Clin Sci, Pediat Unit, Umeå Univ, Umeå, Sweden.
    Lundberg, Elena
    Dept Clin Sci, Pediat Unit, Umeå Univ, Umeå, Sweden.
    Aronson, A. Stefan
    Dept Pediat, Halmstad Cty Hosp, Halmstad, Sweden.
    Gustafsson, Jan
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden.
    Hagenäs, Lars
    Dept Womens & Childrens Hlth, Karolinska Inst, Stockholm, Sweden.
    Ivarsson, Sten-A.
    Dept Pediat, Lund Univ, Malmö, Sweden.
    Jonsson, Björn
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden.
    Ritzen, Martin
    Dept Womens & Childrens Hlth, Karolinska Inst, Stockholm, Sweden.
    Tuvemo, Torsten
    Dept Womens & Childrens Hlth, Uppsala Univ, Uppsala, Sweden.
    Westgren, Ulf
    Dept Pediat, Lund Univ, Malmo, Sweden.
    Westphal, Otto
    Goteborg Pediat Growth Res Ctr, Dept Pediat, Inst Clin Sci, Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Åman, Jan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Growth hormone dose-dependent pubertal growth: a randomized trial in short children with low growth hormone secretion2014In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 82, no 3, p. 158-170Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i. e. idiopathic isolated GH deficiency.

    Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH(33) mu g/kg/day for >= 1 year. They were randomized to receive 67 mu g/kg/day (GH(67)) given as one (GH(67x1); n = 35) or two daily injections (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/day dose (GH(33x1); n = 40). Growth was assessed as height SDS gain for prepubertal, pubertal and total periods, as well as AH SDS versus the population and the midparental height.

    Results: Pubertal height SDS gain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33x1), 0.41, p < 0.05). AH(SDS) was greater on GH(67) (GH(67x1), -0.84; GH(33x2), -0.83) than GH(33) (-1.25, p < 0.05), and height SDS gain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target height SDS.

    Conclusion: Pubertal height SDS gain and AH SDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once-and twice-daily GH(67) regimens. (C) 2014 S. Karger AG, Basel.

  • 5. Alibegovic, A.
    et al.
    Gannerdahl, P.
    Debeer, L.
    Ljungqvist, Olle
    Department of Surgery, Karolinska Hospital, Sweden.
    The effect of alpha 2 receptor agonists on central haemodynamic and blood glucose during hemorrhagic stress in the rat1998In: Surgical Research Communications, ISSN 0882-9233, Vol. 9, no 2-4, p. 151-164Article in journal (Refereed)
    Abstract [en]

    The effect of the selective alpha 2 agonist Mivazerol on catecholamine levels in plasma, and on central hemodynamics and blood glucose levels developments during hemorrhagic stress in rats was investigated. The animals were randomly given either saline, low dose of Mivazerol (0.6 μg/ml) or high dose (2.0 μg/ml) at a rate of 30 μl/100 g/min, beginning the infusions intravenously 30 min before onset and throughout 60 min of hemorrhagic stress. Before hemorrhage, Mivazerol raised mean arterial pressure, and reduced heart rate, adrenaline and noradrenaline levels in a dose dependent fashion. High dose infusion also resulted in an elevation in blood glucose. During hemorrhage, the high dose effectively dampened the catecholamine response. Simultaneously, the same group maintained better mean arterial pressure in response to hemorrhage. Blood glucose levels were elevated to similar levels regardless of treatment. These data indicate that Mivazerol effectively reduced the catecholamine response to severe hemorrhagic stress, while central hemodynamic and blood glucose responses were maintained or improved.

  • 6.
    Alston-Smith, J.
    et al.
    Uppsala University, Biomedical Center, Department of Medicine, Sweden.
    Ljungqvist, Olle
    Ware, J.
    Nilsson Ekdahl, K. N.
    Regulation of rat hepatocyte fructose 1,6-diphosphatase activity during endotoxemia1991In: Surgical Research Communication, ISSN 0882-9233, Vol. 11, no 1-2, p. 67-75Article in journal (Refereed)
  • 7.
    Andersen, Gregers Stig Tig
    et al.
    Steno Diabetes Center, Gentofte, Denmark.
    Thybo, Tanja
    Steno Diabetes Center, Gentofte, Denmark.
    Cederberg, Henna
    Department of Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Steno Diabetes Center, Gentofte, Denmark.
    Esteller, Manel B.
    Cancer Epigenetics and Biology Program, Spanish Biomedical Research Centre Network for Epidemiology and Public Health, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Barcelona, Spain.
    Zorzano, Antonio
    Institute for Research in Biomedicine, Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Carr, Bernadette M.
    Voluntary Health Insurance Board, Dublin, Ireland.
    Walker, Mark G.
    University of Newcastle-on-Tyne, Newcastle, United Kingdom.
    Cobb, Jeff E.
    Metabolon Inc., Durham NC, United States.
    Clissmann, C.
    Pintail Ltd., Dublin, Ireland.
    O'Gorman, Donal J.
    Centre for Preventive Medicine, School of Health and Human Performance, Dublin City University, Dublin, Ireland.
    Nolan, John J.
    Steno Diabetes Center, Gentofte, Denmark.
    The DEXLIFE study methods: identifying novel candidate biomarkers that predict progression to type 2 diabetes in high risk individuals2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 106, no 2, p. 383-389, article id S0168-8227(14)00319-2Article in journal (Refereed)
    Abstract [en]

    The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.

  • 8.
    Andrade, Anenisia C.
    et al.
    Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Gkourogianni, Alexandra
    Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Segerlund, Emma
    Sunderby Hosp, Sunderby, Sweden.
    Werner-Sperker, Antje
    Sunderby Hosp, Sunderby, Sweden.
    Horemuzova, Eva
    Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Dahlgren, Jovanna
    Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Short Stature Due To Two Novel Heterozygous Igf1r Mutations and Response To Gh Treatment2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no Suppl. 1, p. 130-131, article id P1-842Article in journal (Other academic)
  • 9.
    Andrade, Anenisia C.
    et al.
    Division of Pediatric Endocrinology, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Jee, Youn Hee
    Section of Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden.
    New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no 1, p. 22-37Article, review/survey (Refereed)
    Abstract [en]

    Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.

  • 10.
    Arora, Tulika
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espoo, Finland; Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, Helsinki, Finland.
    Pournaras, Dimitri J.
    Department of Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.
    Welbourn, Richard
    Department of Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.
    le Roux, Carel W.
    Diabetes Complications Research Centre, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Gastrosurgical Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicie, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, University of Copenhagen, Copenhagen, Denmark.
    Roux-en-Y Gastric Bypass Surgery Induces Early Plasma Metabolomic and Lipidomic Alterations in Humans Associated with Diabetes Remission2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0126401Article in journal (Refereed)
    Abstract [en]

    Roux-en-Y gastric bypass (RYGB) is an effective method to attain sustained weight loss and diabetes remission. We aimed to elucidate early changes in the plasma metabolome and lipidome after RYGB. Plasma samples from 16 insulin-resistant morbidly obese subjects, of whom 14 had diabetes, were subjected to global metabolomics and lipidomics analysis at pre-surgery and 4 and 42 days after RYGB. Metabolites and lipid species were compared between time points and between subjects who were in remission and not in remission from diabetes 2 years after surgery. We found that the variables that were most discriminatory between time points were decanoic acid and octanoic acid, which were elevated 42 days after surgery, and sphingomyelins (18:1/21:0 and 18:1/23:3), which were at their lowest level 42 days after surgery. Insulin levels were lower at 4 and 42 days after surgery compared with pre-surgery levels. At 4 days after surgery, insulin levels correlated positively with metabolites of branched chain and aromatic amino acid metabolism and negatively with triglycerides with long-chain fatty acids. Of the 14 subjects with diabetes prior to surgery, 7 were in remission 2 years after surgery. The subjects in remission displayed higher pre-surgery levels of tricarboxylic acid cycle intermediates and triglycerides with long-chain fatty acids compared with subjects not in remission. Thus, metabolic alterations are induced soon after surgery and subjects with diabetes remission differ in the metabolic profiles at pre- and early post-surgery time points compared to patients not in remission.

  • 11.
    Arvidsson, Bo
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden; Centre for Health Care Sciences, Örebro County Council, Örebro, Sweden.
    Bodin, Lennart
    Institute of Environmental Medicine, Unit of Intervention and Implementation Research, Karolinska Institute, Stockholm, Sweden.
    Rask, Eva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden.
    Schwarcz, Erik
    Örebro University Hospital. Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden.
    Möller, Margareta
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Centre for Health Care Sciences, Örebro University Hospital, Örebro, Sweden.
    Reference data for bone mineral density in Swedish women using digital X-ray radiometry2013In: Journal of clinical densitometry, ISSN 1094-6950, E-ISSN 1559-0747, Vol. 16, no 2, p. 183-188Article in journal (Refereed)
    Abstract [en]

    During the last decade, digital X-ray radiometry (DXR) has been used to measure bone mineral density (BMD) in the metacarpal bones. The aim of this study was to establish Swedish reference material for bone mass in women, measured in the metacarpal bones with DXR, and compare these data with the data from the manufacturer. A sample of 1440 women aged 20-79yr living in Örebro County was randomly assigned from the population register. Microdose mammography was used (Sectra MDM L30; Sectra Imtec AB, Linköping, Sweden) to measure BMD. Cole's LMS method was used to calculate DXR. Six hundred sixty-nine (48.3%) women participated. Peak bone mass occurred at the age of 43.4yr with a BMD of 0.597g/cm(2) (standard deviation: 0.050). Our Swedish data correlated well with the manufacturer's material. Only among women aged 50-59yr did BMD differ, where the Swedish sample had lower values. The LMS method can be used to describe the DXR data and provide a more detailed picture of bone density distribution. DXR-BMD in Swedish women aged 20-79yr is equivalent to findings from other studies, showing the same distribution of BMD in most age groups except for ages 50-59yr.

  • 12.
    Axelsson, K. F.
    et al.
    Geriatric Medicine, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
    Werling, M.
    Department of Gastrosurgical Research & Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Eliasson, B.
    Department of Molecular a nd Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, sweden.
    Szabo, Eva
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Surgery.
    Näslund, I.
    Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Wedel, H.
    Health Metrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lundh, D.
    School of Bioscience, University of Skövde, Skövde, Sweden.
    Lorentzon, M.
    Geriatric Medicine, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
    Fracture Risk After Gastric Bypass Surgery: A Retrospective Cohort Study2018In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 29, no Suppl. 1, p. S491-S491Article in journal (Other academic)
    Abstract [en]

    Objectives: Gastric bypass surgery constitutes the most common and effective bariatric surgery to treat obesity. Gastric bypass leads to bone oss but fracture risk following surgery has been insufficiently studied. Our objective was to investigate if gastric bypass surgery in obese patients, with and without diabetes, was associated with fracture risk, and if the fracture risk was associated with post-surgery weight loss or insufficient calcium and vitamin D supplementation.

    Methods: Using large databases, 38 971 obese patients undergoing gastric bypass were identified, 7758 with diabetes and 31 213 without. Through multivariable 1:1 propensity score matching, well-balanced controls were identified. The risk of fracture and fall injury was investigated using Cox proportional hazards and flexible parameter models. Fracture risk according to weight loss and degree of calcium and vitamin D supplementation one year post-surgery was investigated.

    Results: 77 942 patients had a median and total follow-up time of 3.1 (IQR 1.7-4.6) and 251 310 person-years, respectively. Gastric bypass was associated with increased risk of any fracture, in patients with diabetes and without diabetes using a multivariable Cox model (HR 1.26, 95%CI 1.05-1.53 and HR 1.32, 95%CI 1.18-1.47, respectively). The risk of fall injury without fracture was also increased after gastric bypass, both in patients with (HR 1.26 95%CI 1.04-1.52) and without diabetes (HR 1.24 95%CI 1.12-1.38). Weight loss or degree of calcium and vitamin D supplementation after gastric bypass were not associated with fracture risk.

    Conclusions: Gastric bypass was associated with an increased risk of fracture and fall injury. Weight loss or calcium and vitamin D supplementation following surgery were not associated with fracture risk. These findings indicate that gastric bypass increases fracture risk, which could at least partly be due to increased susceptibility to falls.

  • 13. Balagopal, P.
    et al.
    Ljungqvist, Olle
    Dept. of Surgery, Karolinska Institute and Hospital, Stockholm, Sweden.
    Nair, K. S.
    Endocrine Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States.
    Skeletal muscle heavy-chain synthesis rate in healthy humans1997In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 272, no 1, p. 45-50Article in journal (Refereed)
    Abstract [en]

    Mixed muscle protein synthetic rate has been measured in humans. These measurements represent the average of synthetic rates of all muscle proteins with variable rates. We determined to what extent the synthesis rate of mixed muscle protein in humans reflects that of myosin heavy chain (MHC), the main contractile protein responsible for the conversion of ATP to mechanical energy as muscle contraction. Fractional synthetic rates of MHC and mixed muscle protein were measured from the increment of [C-13]leucine in these proteins in vastus lateralis biopsy samples taken at 5 and 10 h during a primed continuous infusion of L-[1-C-13]leucine in 10 young healthy subjects. Calculations were done by use of plasma [C-13]ketoisocaproate (KIC) and muscle tissue fluid [C-13]leucine as surrogate measures of leucyl-tRNA. Fractional synthetic rate of MHC with plasma KIC (0.0299 +/- 0.0043%/h) and tissue fluid leucine (0.0443 +/- 0.0056%/h) were only 72 +/- 3% of that of mixed muscle protein (0.0408 +/- 0.0032 and 0.0603 +/- 0.0059%/h, respectively, with KIC and tissue fluid leucine). Contribution of MHC (7 +/- 1 mg . kg(-1) . h(-1)) to synthetic rates of whole body mixed muscle protein (36 +/- 5 mg . kg(-1) . h(-1)) and whole body protein (127 +/- 4 mg . kg(-1) . h(-1)) is only 18 +/- 1 and 5 +/- 1%, respectively. This relatively low contribution of MHC to whole body and mixed muscle protein synthesis warrants direct measurement of synthesis rate of MHC in conditions involving abnormalities of muscle contractile function.

  • 14.
    Bang, P.
    et al.
    Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute and Hospital, Stockholm, Sweden.
    Nygren, J.
    Department of Surgery, Karolinska Institute and Hospital, Stockholm, Sweden.
    Carlsson-Skwirut, C.
    Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute and Hospital, Stockholm, Sweden.
    Thorell, A.
    Department of Surgery, Karolinska Institute and Hospital, Stockholm, Sweden.
    Ljungqvist, Olle
    Department of Surgery, Karolinska Institute and Hospital, Stockholm, Sweden.
    Postoperative induction of insulin-like growth factor binding protein-3 proteolytic activity: relation to insulin and insulin sensitivity1998In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 83, no 7, p. 2509-2515Article in journal (Refereed)
    Abstract [en]

    Increased serum insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) proteolytic activity (IGFBP-3-PA) has been demonstrated in a number of clinical states of insulin resistance, including severe illness, after surgery, and in noninsulin-dependent diabetes mellitus. In the present study we assessed the role of insulin sensitivity in expression of IGFBP-3-PA in serum. In 18 patients studied, a significant increase in IGFBP-3-PA (P < 0.005) was demonstrated after cole-rectal surgery. Eight patients receiving an oral glucose load before surgery demonstrated a significant greater relative increase in IGFBP-3-PA compared with 10 patients not receiving glucose (32.9 +/- 7.1% vs. 8.6 +/- 6.7%, respectively; P < 0.05). Both groups had reduced insulin sensitivity after surgery(-58 +/- 4%; P < 0.0001; n = 18), as determined by hyperinsulinemic, normoglycemic clamps; however, the group not receiving glucose displayed 18% less insulin sensitivity than the oral glucose load group (P < 0.05). Multiple regression analysis demonstrated that the relative changes in IGFBP-3-PA and C peptide levels were inversely correlated (P < 0.05), suggesting that increased IGFBP-3-PA, presumably increasing IGF bioavailability, may be associated with decreased insulin demands. Interestingly, insulin infusion during the 4-h hyperinsulinemic, normoglycemic clamp performed 24 h after surgery (post-op) resulted in a further increase in IGFBP-3-PA in both groups (P < 0.005), whereas no significant responses could be demonstrated during the pre-op clamp. The expression of increased IGFBP-3-PA was accompanied by conversion of endogenous intact 39/42-kDa IGFBP-3 into its 30-kDa fragmented form as determined by Western immunoblotting, and this conversion was virtually complete after the 4-h post-op clamp in patients displaying marked increases in IGFBP-3-PA. Characterization of the IGFBP-3-PA demonstrated that it was specific for IGFBP-3, as no degradation of IGFBP-1 and -2 was detected, and the use of various protease inhibitors demonstrated that serine proteases and possibly matrix metalloproteinases contribute to the increased IGFBP-3-PA level after surgery. We propose that IGF bioavailability may be increased by the induction of IGFBP-3-PA in insulin-resistant subjects, and that insulin regulates IGFBP-3-PA in this state.

  • 15.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    Abstract [en]

    Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

  • 16.
    Beraki, Åsa
    et al.
    Linköping University, Linköping, Sweden.
    Magnusson, Anders
    Clinical Epidemiology and Biostatistic Unit, Örebro University Hospital, Örebro, Sweden.
    Särnblad, Stefan
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Åman, Jan
    Örebro University Hospital. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Samuelsson, Ulf
    Department of Clinical and Experimental Medicine, Division of Pediatrics and Diabetes Research Centre, Linköping University, Linköping, Sweden.
    Increase in physical activity is associated with lower HbA1c levels in children and adolescents with type 1 diabetes: results from a cross-sectional study based on the Swedish pediatric diabetes quality registry (SWEDIABKIDS)2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 105, no 1, p. 119-125Article in journal (Refereed)
    Abstract [en]

    Aims: To evaluate the associations between physical activity (PA) and metabolic control, measured by glycated hemoglobin (HbA1c), in a large group of children and adolescents with type 1 diabetes.

    Methods: Cross-sectional analysis of data from 4655 patients, comparing HbA1c values with levels of physical activity. The data for the children and adolescents were obtained from the Swedish pediatric diabetes quality registry, SWEDIABKIDS. The patients were 7-18 years of age, had type 1 diabetes and were not in remission. Patients were grouped into five groups by frequency of PA.

    Results: Mean HbA1c level was higher in the least physically active groups (PA0: 8.8% +/- 1.5 (72 +/- 16 mmol/mol)) than in the most physically active groups (PA4: 7.7% +/- 1.0 (60 +/- 11 mmol/mol)) (p < 0.001). An inverse dose-response association was found between PA and HbA1c (beta: -0.30, 95%CI: -0.34 to -0.26, p < 0.001). This association was found in both sexes and all age groups, apart from girls aged 7-10 years. Multiple regression analysis revealed that the relationship remained significant (beta: -0.21, 95% CI: -0.25 to -0.18, p < 0.001) when adjusted for possible confounding factors.

    Conclusions: Physical activity seems to influence HbA1c levels in children and adolescents with type 1 diabetes. In clinical practice these patients should be recommended daily physical activity as a part of their treatment.

  • 17.
    Bjornsdottir, Sigridur
    et al.
    Dept Mol Med & Surg, Karolinska Inst, Stockholm, Sweden.
    Sundstrom, Anders
    Dept Clin Epidemiol Unit, Dept Med, Karolinska Inst, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Dept Clin Epidemiol Unit, Dept Med, Karolinska Inst, Stockholm, Sweden.
    Blomqvist, Paul
    Dept Clin Epidemiol Unit, Dept Med, Karolinska Inst, Stockholm, Sweden.
    Kampe, Olle
    Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Bensing, Sophie
    Dept Mol Med & Surg, Karolinska Inst, Stockholm, Sweden; Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Drug Prescription Patterns in Patients With Addison's Disease: A Swedish Population-Based Cohort Study2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 5, p. 2009-2018Article in journal (Refereed)
    Abstract [en]

    Context: There are no published data on drug prescription in patients with Addison's disease ( AD). Objective: Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls. Design and Setting: We conducted a population-based cohort study in Sweden. Patients: Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population. Main Outcome Measure: We determined the ratio of observed to expected number of patients treated with prescribed drugs. Results: Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD. Conclusion: Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.

  • 18.
    Blonde, Lawrence
    et al.
    Department of Endocrinology, Ochsner Medical Center, New Orleans LA, USA.
    Jendle, Johan
    Örebro University, School of Medical Sciences. Endocrine and Diabetes Center, Karlstad Hospital, Karlstad, Sweden.
    Gross, Jorge
    Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
    Woo, Vincent
    Section of Endocrinology and Metabolism, University of Manitoba, Winnipeg MB, Canada.
    Jiang, Honghua
    Lilly Diabetes, Eli Lilly and Company, Indianapolis IN, USA.
    Fahrbach, Jessie L.
    Diabetes, Eli Lilly and Company, Indianapolis IN, USA.
    Milicevic, Zvonko
    Lilly Research Laboratories, Vienna, Austria.
    Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study2015In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 385, no 9982, p. 2057-2066Article in journal (Refereed)
    Abstract [en]

    Background: For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes.

    Methods: We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268.

    Findings: Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (-1·64% [95% CI -1·78 to -1·50], -17·93 mmol/mol [-19·44 to -16·42]) and dulaglutide 0·75 mg (-1·59% [-1·73 to -1·45], -17·38 mmol/mol [-18·89 to -15·87]) than in those receiving glargine (-1·41% [-1·55 to -1·27], -15·41 mmol/mol [-16·92 to -13·90]). The adjusted mean difference versus glargine was -0·22% (95% CI -0·38 to -0·07, -2·40 mmol/mol [-4·15 to -0·77]; p=0·005) for dulaglutide 1·5 mg and -0·17% (-0·33 to -0·02, -1·86 mmol/mol [-3·61 to -0·22]; p=0·015) for dulaglutide 0·75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting.

    Iinterpretation: Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment.

    FUNDING: Eli Lilly and Company.

  • 19.
    Bogl, Leonie H.
    et al.
    Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. Department of Psychology, University of Southern California, Los Angeles CA, United States.
    Kaprio, Jaakko
    Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
    Does the sex of one's co-twin affect height and BMI in adulthood?: A study of dizygotic adult twins from 31 cohorts2017In: Biology of Sex Differences, ISSN 2042-6410, Vol. 8, no 1, article id 14Article in journal (Refereed)
    Abstract [en]

    Background: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs.

    Methods: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese.

    Results: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance.

    Conclusions: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

  • 20.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, University of Navarra, Pamplona, Spain.
    Maukonen, Johanna
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rissanen, Aila
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
    Saarela, Maria
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kaprio, Jaakko
    Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
    Hakkarainen, Antti
    Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Jesper
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Nina
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Pietiläinen, Kirsi H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 9, p. 4169-4179Article in journal (Refereed)
    Abstract [en]

    Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels.

  • 21. Cameron, F. J.
    et al.
    Skinner, T. C.
    de Beaufort, C. E.
    Hoey, H.
    Swift, P. G. F.
    Aanstoot, H.
    Åman, Jan
    Örebro University, School of Health and Medical Sciences.
    Martul, P.
    Chiarelli, F.
    Daneman, D.
    Danne, T.
    Dorchy, H.
    Kaprio, E. A.
    Kaufman, F.
    Kocova, M.
    Mortensen, H. B.
    Njølstad, P. R.
    Phillip, M.
    Robertson, K. J.
    Schoenle, E. J.
    Urakami, T.
    Vanelli, M.
    Ackermann, R. W.
    Skovlund, S. E.
    Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?2008In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 25, no 4, p. 463-468Article in journal (Refereed)
    Abstract [en]

    AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries.

    METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood.

    RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen.

    CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres 

  • 22.
    Carlsson, Lena M. S.
    et al.
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Peltonen, Markku
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Ahlin, Sofie
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Anveden, Åsa
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bouchard, Claude
    Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge LA, United States.
    Carlsson, Björn
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jacobson, Peter
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lönroth, Hans
    Institute of Surgery, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Maglio, Cristina
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Näslund, Ingmar
    Department of Surgery, Örebro University Hospital, Region Örebro län, Örebro, Sweden.
    Pirazzi, Carlo
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Romeo, Stefano
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjöholm, Kajsa
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjöström, Elisabeth
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wedel, Hans
    Nordic School of Public Health, Gothenburg, Sweden.
    Svensson, Per-Arne
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjöström, Lars
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 8, p. 695-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes.

    METHODS: In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.

    RESULTS: During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P< 0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P = 0.002 for the interaction) but not by BMI (P = 0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.

    CONCLUSIONS: Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.)

  • 23.
    Carobbio, Stefania
    et al.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Hagen, Rachel M.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lelliott, Christopher J.
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Slawik, Marc
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Endocrine Research Unit, Medizinische Klinik-Innenstadt, Ludwig-Maximilians University, Munich, Germany.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, , Madrid, Spain.
    Tan, Chong-Yew
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Sicard, Audrey
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France.
    Atherton, Helen J.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Barbarroja, Nuria
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Hospital Virgen de la Victoria, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Malaga, Spain.
    Bjursell, Mikael
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Bohlooly-Y, Mohammad
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Virtue, Sam
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Tuthill, Antoinette
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lefai, Etienne
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Laville, Martine
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Wu, Tingting
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Considine, Robert V.
    Division of Endocrinology and Metabolism, School of Medicine, Indiana University, Indianapolis IN, United States.
    Vidal, Hubert
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Langin, Dominique
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France; Laboratory of Clinical Biochemistry, Toulouse, France.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Department of Medicine, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
    Tinahones, Francisco J.
    Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
    Fernandez-Real, Jose Manuel
    Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain.
    Griffin, Julian L.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Sethi, Jaswinder K.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    López, Miguel
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 11, p. 3697-3708Article in journal (Refereed)
    Abstract [en]

    The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

  • 24.
    Cheng, Helen
    et al.
    Department of Psychology, University College London, London, United Kingdom; ESRC Centre for Learning and Life Chances in Knowledge Economies and Societies, Institute of Education, University of London, London, United Kingdom .
    Treglown, Luke
    Department of Psychology, University College London, London, United Kingdom; Department of Psychology, University of Bath, Bath, United Kingdom .
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Research Department of Epidemiology and Public Health, UCL, London, United Kingdom .
    Furnham, Adrian
    Department of Psychology, University College London, London, United Kingdom; Norwegian Business School, Oslo, Norway .
    Associations between familial factor, trait conscientiousness, gender and the occurrence of type 2 diabetes in adulthood: evidence from a British cohort2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0122701Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate social, familial, and psychological factors in influencing the occurrence of type 2 diabetes in adulthood.

    Method: Some 17,415 babies born in Great Britain in 1958 and followed up at 7, 11, 33, and 50 years of age. The prevalence of type 2 diabetes at age 50 years was the outcome measure.

    Results: Some 5,032 participants with data on parental social class, childhood cognitive ability tests scores at age 11 years, educational qualifications at age 33 years, personality traits, occupational levels, and type 2 diabetes (all measured at age 50 years) were included in the study. Available information also included whether cohort members' parents or siblings had diabetes. Using logistic regression analyses, results showed that sex (OR= 0.63: 0.42-0.92, p<. 05), family history (OR= 3.40: 1.76-6.55, p<. 01), and trait conscientiousness (OR= 0.76: 0.64-0.90, p<. 001) were all significantly and independently associated with the occurrence of type 2 diabetes in adulthood. It appears that the occurrence of type 2 diabetes is greater among men than women (4.3% vs 2.5%).

    Conclusion: Familial (genetic and non-genetic) and psychological factors are significantly associated with the prevalence of type 2 diabetes in adulthood.

  • 25.
    Coenen Schimke, J. M.
    et al.
    Endocrine Research Unit, Division of Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
    Ljungqvist, Olle
    Department of Medicine, University of Vermont, Burlington, VT, USA.
    Sarkar, G.
    Department of Medicine, University of Vermont, Burlington, VT, USA.
    Conover, C. A.
    Endocrine Research Unit, Division of Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
    Nair, K. S.
    Endocrine Research Unit, Division of Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
    A quantitative PCR measurement of messenger RNA expression of IGF-I, IGF-II and IGFBP-5 in human skeletal muscle1999In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 9, no 3, p. 179-186Article in journal (Refereed)
    Abstract [en]

    Insulin-like growth factor-I and -II (IGF-I and IGF-II) and their binding proteins are important components in growth promotion and tissue maintenance. We determined the presence of IGF-I, -II, and binding protein 5 (IGFBP-5) gene expression in human skeletal muscle and that mRNA abundance is not altered by nutrients and insulin. In the first protocol, (control) subjects were given water. In the second protocol, half of these subjects drank Polycose (carbohydrate) and the remaining subjects drank equal calories as a mixed meal. Quadriceps muscle biopsies were taken at 10 h. A semi-quantitative polymerase chain reaction was designed to measure gene expression. IGF-I, IGF-II and IGFBP-5 mRNA are present in adult human skeletal muscle, but no significant changes between meal groups were observed for IGF-I, IGF-II or IGFBP-5 mRNA levels, indicating that the expression of these genes are not altered acutely by nutrients and insulin.

  • 26.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Ohlson, Anna-Lena
    Department of Laboratory Medicine, Pathology, University Hospital Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giunchi, Francesca
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Rider, Jennifer R.
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Fiorentino, Michelangelo
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 1, p. 40-47Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer.

    METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area.

    RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart.

    CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.

  • 27.
    de Beaufort, Carine E.
    et al.
    Pediat Clin, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg.
    Lange, Karin
    Dept Med Psychol, Hannover Medical School, Hannover, Germany.
    Swift, Peter G. F.
    Childrens Hosp, Leicester Royal Infirmary, Leicester, England..
    Åman, Jan
    Örebro University Hospital. Dept Pediat, Örebro University Hospital, Örebro, Sweden.
    Cameron, Fergus
    Dept Endocrinol & Diabet, Royal Childrens Hosp, Parkville Vic, Australia.
    Castano, Luis
    Endocrinol & Diabet Res Grp, Hosp Cruces, Univ Basque Country, Baracaldo, Spain.
    Dorchy, Harry
    Diabetol Clin, Univ Hosp Reine Fabiola, Brussels, Belgium.
    Fisher, Lynda K.
    Dept Endocrinol & Diabet, Childrens Hosp Los Angeles, Los Angeles CA, USA..
    Hoey, Hilary
    Natl Childrens Hosp, Univ Dublin Trinity Coll, Dublin, Ireland.
    Kaprio, Eero
    Dept Paediat, Peijas Hosp, Helsinki, Finland.
    Kocova, Mirjana
    Dept Endocrinol & Genet, Univ Pediat Clin, Skopje, Macedonia.
    Neu, Andreas
    Clin Children & Adolescence, Univ Tubingen, Tubingen, Germany.
    Njolstad, Pal R.
    Dept Clin Med, Univ Bergen, Bergen, Norway; Dept Pediat, Haukeland Hosp, Bergen, Norway.
    Phillip, Moshe
    Natl Ctr Childhood Diabet, Schneiders Med Ctr Israel, Petah Tiqwa, Israel.
    Schoenle, Eugen
    Dept Diabet & Endocrinol, Univ Childrens Hosp, Zurich, Switzerland.
    Robert, Jean J.
    Dept Childhood & Adolescent Diabet, Hop Necker Enfants Malad, Paris, France.
    Urukami, Tatsuhiko
    Sch Med, Nihon Univ, Tokyo, Japan.
    Vanelli, Maurizio
    Pediat Clin, Ctr Diabetol, Parma, Italy.
    Danne, Thomas
    Krankenhaus Bult, Hannover, Germany.
    Barrett, Tim
    Inst Child Hlth, Univ Birmingham, Birmingham, England; Birmingham Childrens Hosp, Univ Birmingham, Birmingham, England.
    Chiarelli, Franco
    Pediat Clin, Osped Policlin, Chieti, Italy.
    Aanstoot, Henk J.
    Ctr Pediat & Adolescent Diabet Care & Res, Rotterdam, Netherlands.
    Mortensen, Henrik B.
    Herlev Hosp, Dept Pediat, Herlev, Denmark; Fac Hlth Sci, Univ Copenhagen, Copenhagen, Denmark.
    Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 20092013In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 14, no 6, p. 422-428Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether center differences in glycemic control are present in prepubertal children <11yr with type 1 diabetes mellitus. Research Design and Methods: This cross-sectional study involved 18 pediatric centers worldwide. All children, <11 y with a diabetes duration 12months were invited to participate. Case Record Forms included information on clinical characteristics, insulin regimens, diabetic ketoacidosis (DKA), severe hypoglycemia, language difficulties, and comorbidities. Hemoglobin A1c (HbA1c) was measured centrally by liquid chromatography (DCCT aligned, range: 4.4-6.3%; IFFC: 25-45mmol/mol). Results: A total of 1133 children participated (mean age: 8.0 +/- 2.1 y; females: 47.5%, mean diabetes duration: 3.8 +/- 2.1 y). HbA1c (overall mean: 8.0 +/- 1.0%; range: 7.3-8.9%) and severe hypoglycemia frequency (mean 21.7 events per 100 patient-years), but not DKA, differed significantly between centers (p<0.001 resp. p=0.179). Language difficulties showed a negative relationship with HbA1c (8.3 +/- 1.2% vs. 8.0 +/- 1.0%; p = 0.036). Frequency of blood glucose monitoring demonstrated a significant but weak association with HbA1c (r=-0.17; p<0.0001). Although significant different HbA1c levels were obtained with diverse insulin regimens (range: 7.3-8.5%; p<0.001), center differences remained after adjusting for insulin regimen (p<0.001). Differences between insulin regimens were no longer significant after adjusting for center effect (p=0.199). Conclusions: Center differences in metabolic outcomes are present in children <11yr, irrespective of diabetes duration, age, or gender. The incidence of severe hypoglycemia is lower than in adolescents despite achieving better glycemic control. Insulin regimens show a significant relationship with HbA1c but do not explain center differences. Each center's effectiveness in using specific treatment strategies remains the key factor for outcome.

  • 28.
    Derakhshan, Arash
    et al.
    Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, The Netherlands; Department of internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
    Shu, Huan
    Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, Sweden.
    Broeren, Maarten A. C.
    Laboratory of Clinical Chemistry and Haematology, Máxima Medical Centre, Veldhoven, De Run, The Netherlands.
    de Poortere, Ralph A.
    Laboratory of Clinical Chemistry and Haematology, Máxima Medical Centre, Veldhoven, De Run, The Netherlands.
    Wikström, Sverre
    Örebro University, School of Medical Sciences.
    Peeters, Robin P.
    Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, The Netherlands; Department of internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
    Demeneix, Barbara
    Laboratoire d'Evolution des Régulations Endocriniennes, Muséum National d'Histoire Naturelle, Paris, France.
    Bornehag, Carl-Gustaf
    Division of Public Health Sciences, Karlstad University, Karlstad, Sweden; Icahn School of Medicine at Mount Sinai, New York City NY, USA.
    Korevaar, Tim I. M.
    Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, The Netherlands; Department of internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
    Reference ranges and determinants of thyroid function during early pregnancy: the SELMA study2018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 9, p. 3548-3556Article in journal (Refereed)
    Abstract [en]

    Context: Establishing reference ranges as well as identifying and quantifying the determinants of thyroid function during pregnancy is important for proper clinical interpretation and optimizing research efforts. However, such data are sparse, specifically for (F)T3 measurements and most studies do not take into account thyroid antibodies or hCG.

    Objective: To determine reference ranges and to identify/quantify determinants of TSH, FT4, FT3, TT4 and TT3.

    Design, Setting and Participants: This study included 2,314 participants of the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study, a population-based prospective pregnancy cohort of mother-child pairs. Reference ranges were calculated by 2.5-97.5th percentiles after excluding TPOAb and/or TgAb positive women.

    Intervention: None.

    Main Outcome Measures: TSH, FT4, FT3, TT4 and TT3 in prenatal serum.

    Results: After exclusion of TPOAb positive women, reference range were: TSH: 0.11-3.48 mU/L, FT4: 11.6-19.4 pmol/L, FT3: 3.72-5.92 pg/mL, TT4: 82.4-166.2 pmol/L and TT3: 1.28-2.92 nmol/L. Additional exclusion of TgAb positive women did not change the reference ranges substantially. Exposure to tobacco smoke, as assessed by questionnaires and serum cotinine, was associated with lower TSH and higher FT3 and TT3. BMI and gestational age were the main determinants of TSH (only for BMI), FT4, FT3, TT4 and TT3.

    Conclusions: We show that the exclusion of TgAb positive women on top of excluding TPOAb positive women hardly affects clinical reference ranges. We identified various relevant clinical determinants of TSH, FT4, FT3, TT4 and TT3 which could reflect endocrine disrupting effects and/or effects on thyroid hormone transport or deiodination.

  • 29. Devlieger, Roland
    et al.
    Fadl, Helena
    Örebro University, School of Medical Sciences.
    Deruelle, Philippe
    Assessment of fetal and neonatal growth (including growth pattern in diabetes)2016Conference paper (Refereed)
  • 30.
    Elfström, Peter
    et al.
    Örebro University, School of Health and Medical Sciences.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Kämpe, Olle
    Uppsala Universitet.
    Ekbom, Anders
    Karolinska Institutet.
    Ludvigsson, Jonas F.
    Risk of primary adrenal insufficiency in patients with celiac disease2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 9, p. 3595-3598Article in journal (Refereed)
    Abstract [en]

    Objectives: Earlier research has suggested a positive association between Addison’s disease (AD) and celiac disease (CD).Wehave here investigated the risk of AD in individuals with CD from a general population cohort.Methods: Through the Swedish national registers we identified 14,366 individuals with a diagnosis of CD (1964–2003) and 70,095 reference individuals matched for age, sex, calendar year, and county of residence. We used Cox regression to estimate hazard ratios (HRs) for subsequent AD. Analyses were restricted to individuals with more than 1 yr of follow-up and without AD prior to study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for CD in individuals with prior AD.Results: There was a statistically significantly positive association between CD and subsequent AD [HR _ 11.4; 95% confidence interval (CI) _ 4.4 –29.6]. This risk increase was seen in both children and adults and did not change with adjustment for diabetes mellitus or socioeconomic status. When we restricted reference individuals to inpatients, the adjusted HR for AD was 4.6 (95% CI _ 1.9 –11.4). Individuals with prior AD were at increased risk of CD (odds ratio _ 8.6; 95% CI _ 3.4 –21.8).Conclusions: This study found a highly increased risk of AD in individuals with CD. This relationship was independent of temporal sequence. We therefore recommend that individuals with AD should be screened for CD. We also suggest an increased awareness of AD in individuals with CD.

  • 31.
    Elfström, Peter
    et al.
    Örebro University, School of Health and Medical Sciences.
    Montgomery, Scott M.
    Kämpe, Olle
    Ekbom, Anders
    Ludvigsson, Jonas F.
    Risk of Thyroid Disease in Individuals with Celiac Disease2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 10, p. 3915-3921Article in journal (Refereed)
    Abstract [en]

    Background: It has been suggested that celiac disease is associated with thyroid disease. Earlier studies, however, have been predominately cross-sectional and have often lacked controls. There is hence a need for further research. In this study, we estimated the risk of thyroid disease in individuals with celiac disease from a general population cohort.Methods: A total of 14,021 individuals with celiac disease (1964–2003) and a matched reference population of 68,068 individuals were identified through the Swedish national registers. Cox regression estimated the risk of thyroid disease in subjects with celiac disease. Analyses were restricted to individuals with a follow-up ofmorethan 1 yr and withnothyroid disease before study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for subsequent celiac disease in individuals with thyroid disease.Results: Celiac disease was positively associated with hypothyroidism [hazard ratio (HR)_4.4;95% confidence interval (CI) _ 3.4 –5.6; P _ 0.001], thyroiditis (HR _ 3.6; 95% CI _1.9–6.7; P _ 0.001) and hyperthyroidism (HR_2.9;95%CI_2.0–4.2; P_0.001). The highest risk estimates were found in children (hypothyroidism, HR _ 6.0 and 95% CI _ 3.4 –10.6; thyroiditis, HR _ 4.7 and 95% CI _ 2.1–10.5; hyperthyroidism, HR _ 4.8 and 95% CI _ 2.5–9.4). In post hoc analyses, where the reference population was restricted to inpatients, the adjusted HR was 3.4 for hypothyroidism (95% CI_2.7– 4.4; P_0.001), 3.3 for thyroiditis(95%CI_1.5–7.7; P_0.001), and 3.1 for hyperthyroidism (95% CI _ 2.0–4.8; P _ 0.001).Conclusion: Celiac disease is associated with thyroid disease, and these associations were seen regardless of temporal sequence. This indicates shared etiology and that these individuals are more susceptible to autoimmune disease.

  • 32.
    Eliasson, Bjorn
    et al.
    Dept Mol & Clin Med, Univ Gothenburg, Gothenburg, Sweden; Dept Med, Sahlgrenska Univ Hosp, Gothenburg, Sweden.
    Liakopoulos, Vasileios
    Dept Mol & Clin Med, Univ Gothenburg, Gothenburg, Sweden.
    Franzen, Stefan
    Natl Diabetes Register, Registercentrum Västra Götaland, Gothenburg, Sweden.
    Näslund, Ingmar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Dept Surg, Örebro University Hospital, Örebro, Sweden.
    Svensson, Ann-Marie
    Dept Mol & Clin Med, Univ Gothenburg, Gothenburg, Sweden; Natl Diabetes Register, Registercentrum Västra Götaland, Gothenburg, Sweden.
    Ottosson, Johan
    Dept Surg, Örebro University Hospital, Örebro, Sweden.
    Gudbjornsdottir, Soffia
    Dept Mol & Clin Med, Univ Gothenburg, Gothenburg, Sweden; Natl Diabetes Register, Registercentrum Västra Götaland, Gothenburg, Sweden.
    Cardiovascular disease and mortality in patients with type 2 diabetes after bariatric surgery in Sweden: a nationwide, matched, observational cohort study2015In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 3, no 11, p. 847-854Article in journal (Refereed)
    Abstract [en]

    Background In patients with diabetes and obesity specifically, no studies have examined mortality after bariatric surgery. We did a nationwide study in Sweden to examine risks of cardiovascular disease and mortality in patients with obesity and diabetes who had undergone bariatric surgery (Roux-en-Y gastric bypass [RYGB]). Methods In this nationwide, matched, observational cohort study, we merged data for patients who had undergone RYGB registered in the Scandinavian Obesity Surgery Registry with other national databases, and identified matched controls (on the basis of sex, age, BMI, and calendar time [year]) who had not undergone bariatric surgery from the National Diabetes Registry. We assessed risks of cardiovascular disease and death using a Cox proportional-hazards regression model and other methods to examine the treatment effect while accounting for residual confounding. Primary outcomes were total mortality, cardiovascular death, and fatal or non-fatal myocardial infarction. Findings Between Jan 1, 2007, and Dec 31, 2014, we obtained data for 6132 patients who had undergone RYGB and 6132 control patients who had not. Median follow-up was 3.5 years (IQR 2.1-4.7). We noted a 58% relative risk reduction (hazard ratio [HR] 0.42, 95% CI 0.30-0.57; p< 0.0001) in overall mortality in the RYGB group compared with the controls. The risk of fatal or non-fatal myocardial infarction was 49% lower (HR 0.51, 0.29-0.91; p= 0.021) and that of cardiovascular death was 59% lower (0.41, 0.19-0.90; p= 0.026) in the RYGB group than in the control group. 5 year absolute risks of death were 1.8% (95% CI 1.5-2.2) in the RYGB group and 5.8% (5.0-6.8) in the control group. Interpretation Our findings provide support for the benefits of RYGB surgery for patients with obesity and type 2 diabetes. The causes of these beneficial effects may be the weight reduction per se, changes in physiology and metabolism, improved care and treatment, improvements in lifestyle and risk factors, or combinations of these factors.

  • 33.
    Eliman, A.
    et al.
    Department of Paediatrics, Endocrine Research Unit, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Tjäder, I.
    Department of Anaesthesiology and Intensive Care, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Norgren, S.
    Department of Paediatrics, Endocrine Research Unit, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Wernerman, J.
    Department of Anaesthesiology and Intensive Care, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Essén, P.
    Department of Anaesthesiology and Intensive Care, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Ljungqvist, Olle
    Department of Surgery, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Marcus, C.
    Department of Paediatrics, Endocrine Research Unit, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
    Totalparenteral nutrition after surgery rapidly increases serum leptin levels2001In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 144, no 2, p. 123-128Article in journal (Refereed)
    Abstract [en]

    Objective: In humans, leptin is regulated by long-term changes in energy intake. However, short-term regulation of serum leptin by nutrients has been difficult to show. The aim of this study was to investigate whether short periods of fasting and stress sensitise the leptin response to nutrients.

    Subjects and experimental protocol: Fourteen patients of normal weight undergoing elective open cholecystectomy were randomised into two groups. One group received saline infusion during surgery and for 24 h postoperatively. The other group also received saline during the surgical procedure, but total parenteral (TPN) was started immediately after surgery. Blood samples were drawn before as well as 2, 4, 8, 16, and 24 h after the start of surgery to determine the serum levels of leptin and other hormones.

    Results: Postoperative TPN induced a significant rise in serum leptin within 6 h, reaching a more than fourfold increase within 14 h (P < 0.001). Serum glucose and insulin levels increased within 2 h. Growth hormone and IGF-1 serum levels also increased significantly in the group receiving TPN. Serum cortisol levels increased postoperatively in both groups, which may explain why no significant reduction in serum leptin was observed in the group receiving saline. Free tri-iodothyronine (T3) decreased in both groups, while catecholamines were similar in the groups.

    Conclusion: During fasting and surgical stress, nutrients rapidly increased the serum leptin levels in humans in a manner similar to that previously reported in rodents. This may be mediated by increases in serum glucose, insulin and cortisol.

  • 34.
    Eriksson, Jan W.
    et al.
    Department of Medicine, Umeå University Hospital, Umeå, Sweden; Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; AstraZeneca R&D, Mölndal, Sweden.
    Jansson, Per-Anders
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carlberg, Bo
    Department of Medicine, Umeå University Hospital, Umeå, Sweden.
    Hägg, Anders
    Department of Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Kurland, Lisa
    Department of Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Svensson, Maria K.
    Department of Medicine, Umeå University Hospital, Umeå, Sweden; Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ahlström, Håkan
    Department of Radiology, Uppsala University Hospital, Uppsala, Sweden.
    Ström, Conny
    Department of Radiology, Umeå University Hospital, Umeå, Sweden.
    Lönn, Lars
    Department of Radiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Faculty of Health Sciences, Rigshospitalet, Copenhagen, Denmark.
    Öjbrandt, Kristina
    Department of Medicine, Umeå University Hospital, Umeå, Sweden.
    Johansson, Lars
    Department of Radiology, Uppsala University Hospital, Uppsala, Sweden; AstraZeneca R&D, Mölndal, Sweden.
    Lind, Lars
    Department of Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 52, no 6, p. 1030-1037Article in journal (Refereed)
    Abstract [en]

    Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P<or=0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.

  • 35.
    Fadl, Helena E.
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology, Örebro University Hospital, Örebro, Sweden.
    Simmons, David
    School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia.
    Trends in diabetes in pregnancy in Sweden 1998-20122016In: BMJ Open Diabetes Research & Care, ISSN 2052-4897, Vol. 4, no 1, article id e000221Article in journal (Refereed)
    Abstract [en]

    Objective: Diabetes in pregnancy has been shown to increase in parallel with the increasing prevalence of obesity. In this national population-based study, we analyzed the trends for gestational diabetes mellitus (GDM), type 1 diabetes in pregnancy, and type 2 diabetes in pregnancy in Sweden between 1998 and 2012.

    Research design and methods: A population-based cohort study using the Swedish national medical birth registry data. The time periods were categorized into 3-year intervals and adjusted for maternal body mass index (BMI), ethnicity, and age in a logistic regression.

    Results: Each type of diabetes increased over the studied 15-year period. Type 1 diabetes increased by 33.2% (22.2-45.3) and type 2 diabetes by 111% (62.2-174.4) in the adjusted model. Nordic women had the highest prevalence of type 1 diabetes (0.47%) compared with other ethnic groups. The increase in GDM and, to a lesser extent, type 2 diabetes was explained by country of birth, BMI, and maternal age. The prevalence of GDM in Nordic women (0.7-0.8%) did not increase significantly over the time period.

    Conclusions: All types of diabetes in pregnancy increased over the 15-year time period in Sweden. Maternal pre-pregnancy BMI remains the key factor explaining the increase in GDM/type 2 diabetes. How to turn around the growing prevalence of diabetes in pregnancy, with its short-term and long-term health effects on both mother and child, requires population-based interventions that reduce the likelihood of entering pregnancy with a raised BMI.

  • 36.
    Fadl, Helena
    et al.
    Örebro University Hospital. Department of Obstetrics and Gynaecology, Örebro University Hospital, Örebro, Sweden.
    Magnuson, A.
    Östlund, Ingrid
    Örebro University Hospital. Department of Obstetrics and Gynaecology, Örebro University Hospital, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Hanson, Ulf
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Schwarcz, Erik
    Örebro University, School of Health Sciences. Department of Internal Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study2014In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 121, no 12, p. 1530-1536Article in journal (Refereed)
    Abstract [en]

    Objective: To identify if gestational diabetes mellitus (GDM) is a clinically useful marker of future cardiovascular disease (CVD) risk and if GDM combined with other risks (smoking, hypertension or body mass) identifies high-risk groups.

    Design: Population-based matched case-control study.

    Setting: National Swedish register data from 1991 to 2008.

    Population: A total of 2639 women with a cardiovascular event and matched controls.

    Methods: Conditional logistic regression examined associations with CVD before and after adjustment for conventional risk factors and confounders. Effect modification for the association of GDM with CVD by body mass index (BMI), smoking and chronic hypertension was assessed by stratification and interaction testing. Adjustment for diabetes post-pregnancy evaluated its mediating role.

    Main outcome measures: Inpatient diagnoses or causes of death identifying ischemic heart disease, ischemic stroke, atherosclerosis or peripheral vascular disease.

    Results: The adjusted odds ratios (and 95% confidence intervals) for the association of CVD with GDM are 1.51 (1.07-2.14), 2.23 (2.01-2.48) for smoking, 1.98 (1.71-2.29) for obesity and 5.10 (3.18-8.18) for chronic hypertension. In stratified analysis the association of CVD with GDM was only seen among women with BMI 25, with an odds ratio of 2.39 (1.39-4.10), but only women with a BMI <30 accounted for this increased risk. Adjustment for post-pregnancy diabetes attenuated it somewhat to 1.99 (1.13-3.52).

    Conclusions: In the absence of other recognised cardiovascular risk factors, such as smoking, obesity or chronic hypertension, GDM is a useful marker of raised CVD risk among women with BMI between 25 and 29.

  • 37.
    Falhammar, Henrik
    et al.
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Juhlin, Carl Christofer
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Barner, Caroline
    Department of Medicine, Capio S:t Görans Hospital, Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Karefylakis, Christos
    Örebro University, School of Medical Sciences. Department of Diabetes, Endocrinology and Metabolism.
    Calissendorff, Jan
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Riedel's thyroiditis: clinical presentation, treatment and outcomes2018In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 60, no 1, p. 185-192Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Riedel´s thyroiditis (RT) is a rare inflammatory disease of the thyroid gland, causing compression and fibrosis of adjacent tissues. Typically the goiter is hard and firm. Hoarseness, dyspnea, and dysphagia may be present.

    METHODS: We retrospectively reviewed all patients known by us with RT in addition to all patients with appropriate ICD-10 codes evaluated at the Karolinska University Hospital 2003-2015. Clinical, biochemical, and histological data of patients with RT were recorded in detail. Histological preparations were re-examined when available.

    RESULTS: RT was diagnosed in six patients. Five were females and the median age at first presentation was 50 years (25-81 years). Median follow-up time was 3.75 years (1-22 years). At diagnosis five had hypothyroidism. Four had extrathyroidal manifestations, and one of these had also distant fibrosis. One patient had a clear IgG4/IgG ratio over 40%. One patient was treated with tracheostomy, one with isthmectomy and one with total thyroidectomy. Four had been treated with glucocorticoids, four with tamoxifen, and two with both drugs. One had also been treated with mycophenolate mofetil combined with Rituximab. At the end of follow-up four was doing fine, one had recurrent episodes of inflammation and one had died of possible complications to RT.

    CONCLUSION: It is important to recognize RT and give adequate treatment. Steroids are still the mainstay of therapy but other medications against fibrosclerosis can be considered. Wakefulness of other fibrosing manifestations is essential. Immunohistochemistry can show whether IgG-4 plasma cells are increased which could lead to fibrosis in other organs.

  • 38.
    Fang, Xin
    et al.
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Liang, Chun
    Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
    Li, Mei
    Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Fall, Katja
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Aaseth, Jan
    Faculty of Public Health, Hedmark University College, Elverum, Norway; Kongsvinger Hospital Division, Innlandet Hospital Trust, Kongsvinger, Norway.
    Cao, Yang
    Örebro University, School of Medical Sciences. Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Dose-response relationship between dietary magnesium intake and cardiovascular mortality: A systematic review and dose-based meta-regression analysis of prospective studies2016In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 64-73Article in journal (Refereed)
    Abstract [en]

    Background: Although epidemiology studies have reported the relationship, including a dose-response relationship, between dietary magnesium intake and risk of cardiovascular disease (CVD), the risk for CVD mortality is inconclusive and the evidence for a dose-response relationship has not been summarized.

    Objective: We conducted a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the association of dietary magnesium intake with risk of CVD mortality and describe their dose-response relationship.

    Design: We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to August 2015, and reviewed references lists of retrieved articles. We included population-based studies that reported mortality risks, i.e. relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) of CVD mortality or cause-specific CVD death. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines.

    Results: Out of 3002 articles, 9 articles from 8 independent studies met the eligibility criteria. These studies comprised 449,748 individuals and 10,313 CVD deaths. Compared with the lowest dietary magnesium consumption group in the population, the risk of CVD mortality was reduced by 16% in women and 8% in men. No significant linear dose-response relationship was found between increment in dietary magnesium intake and CVD mortality across all the studies. After adjusting for age and BMI, the risk of CVD mortality was reduced by 24-25% per 100 mg/d increment in dietary magnesium intake in women of all the participants and in all the US participants.

    Conclusion: Although the combined data confirm the role of dietary magnesium intake in reducing CVD mortality, the dose-response relationship was only found among women and in US population.

  • 39.
    Foerster, Jana
    et al.
    Department of Epidemiology, German Institute of Human Nutrition Potsdam–Rehbruecke, Nuthetal, Germany.
    Hyötyläinen, Tuulia
    Systems Medicine, Steno Diabetes Centre, Gentofte, Denmark.
    Oresic, Matej
    Systems Medicine, Steno Diabetes Centre, Gentofte, Denmark.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam–Rehbruecke, Nuthetal, Germany.
    Serum Lipid and Serum Metabolite Components in relation to anthropometric parameters in EPIC-Potsdam participants2015In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 64, no 10, p. 1348-58Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIM: Lipidomic and metabolomic techniques become more and more important in human health research. Recent developments in analytical techniques enable the investigation of high amounts of substances. The high numbers of metabolites and lipids that are detected with among others mass spectrometric techniques challenge in most cases the statistical processes to bring out stable and interpretable results. This study targets to use the novel non-established statistical method treelet transform (TT) to investigate high numbers of metabolites and lipids and to compare the results with the established method principal component analysis (PCA). Serum lipid and metabolite profiles are investigated regarding their association to anthropometric parameters associated to obesity.

    METHODS: From 226 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Potsdam study blood samples were investigated with an untargeted metabolomics approach regarding serum metabolites and lipids. Additionally, participants were surveyed anthropometrically to assess parameters of obesity, such as body mass index (BMI), waist-to-hip-ratio (WHR) and body fat mass. TT and PCA are used to generate treelet components (TCs) and factors summarizing serum metabolites and lipids in new, latent variables without too much loss of information. With partial correlations TCs and factors were associated to anthropometry under the control for relevant parameters, such as sex and age.

    RESULTS: TT with metabolite variables (p=121) resulted in 5 stable and interpretable TCs explaining 18.9% of the variance within the data. PCA on the same variables generated 4 quite complex, less easily interpretable factors explaining 37.5% of the variance. TT on lipidomic data (p=353) produced 3 TCs as well as PCA on the same data resulted in 3 factors; the proportion of explained variance was 17.8% for TT and 39.8% for PCA. In both investigations TT ended up with stable components that are easier to interpret than the factors from the PCA. In general, the generated TCs and factors were similar in their structure when the factors are considered regarding the original variables loading high on them. Both TCs and factors showed associations to anthropometric measures.

    CONCLUSIONS: TT is a suitable statistical method to generate summarizing, latent variables in data sets with more variables than observations. In the present investigation it resulted in similar latent variables compared to the established method of PCA. Whereby less variance is explained by the summarizing constructs of TT compared to the factors of PCA, TCs are easier to interpret. Additionally the resulting TCs are quite stable in bootstrap samples.

  • 40.
    Fraser, Abigail
    et al.
    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lawlor, Debbie A
    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Maternal diabetes in pregnancy and offspring cognitive ability: sibling study with 723,775 men from 579,857 families2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 1, p. 102-109Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The aim of this study was to investigate the association between maternal diabetes in pregnancy and offspring cognitive ability and also to assess whether the association was due to intrauterine mechanisms or shared familial characteristics.

    METHODS: We linked national registers and conducted a prospective cohort study of singleton Swedish-born men to explore associations between maternal pregnancy diabetes and educational achievement at age 16 years, the age of completing compulsory education in Sweden (n = 391,545 men from 337,174 families, graduating in 1988-1997 and n = 326,033 men from 282,079 families, graduating in 1998-2009), and intelligence quotient (IQ) at the mandatory conscription examination at 18 years of age (n = 664,871 from 543,203 families).

    RESULTS: Among non-siblings, maternal diabetes in pregnancy was associated with lower offspring cognitive ability even after adjustment for maternal age at birth, parity, education, early-pregnancy BMI, offspring birth year, gestational age and birthweight. For example, in non-siblings, the IQ of men whose mothers had diabetes in their pregnancy was on average 1.36 points lower (95% CI -2.12, -0.60) than men whose mothers did not have diabetes. In comparison, we found no such association within sibships (mean difference 1.70; 95% CI -1.80, 5.21).

    CONCLUSIONS/INTERPRETATION: The association between maternal diabetes in pregnancy and offspring cognitive outcomes is likely explained by shared familial characteristics and not by an intrauterine mechanism.

  • 41. Fritz, Tomas
    et al.
    Krämer, David K.
    Karlsson, Håkan K. R.
    Galuska, Dana
    Engfeldt, Peter
    Örebro University, School of Health and Medical Sciences.
    Zierath, Juleen R.
    Krook, Anna
    Low-intensity exercise increases skeletal muscle protein expression of PPARdelta and UCP3 in type 2 diabetic patients2006In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 22, no 6, p. 492-498Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Physical exercise provides health benefits for people with type 2 diabetes mellitus, partly by enhancing skeletal muscle insulin action. We tested the hypothesis that changes in expression of key genes in skeletal muscles relate to exercise-induced improvements in type 2 diabetic patients. METHODS: We determined mRNA expression of 20 selected genes following a self-supervised program of walking (> 150 min per week) over a 4-month period. RESULTS: This level of physical activity improved clinical parameters in approximately half the participants, as determined by reduced hypertension and enhanced insulin sensitivity (defined by reduced plasma-insulin levels and improved homeostasis model assessment (HOMA)). Skeletal muscle mRNA expression of Cbl-associated protein (CAP), diacylglycerol kinase (DGK)delta, uncoupling protein (UCP) 3, nuclear respiratory factor (NRF)-1, and peroxisome proliferator-activated receptor (PPAR)delta tended to increase in type 2 diabetic patients with an improved clinical profile. Skeletal muscle protein expression of PPARdelta and UCP3 was increased significantly after physical exercise in patients with an improved clinical profile, but were unchanged in patients who did not show exercise-mediated improvements in clinical parameters. CONCLUSIONS: This study provides clinical evidence that improvements in insulin sensitivity can be achieved in type 2 diabetic patients after individually executed low-intensity exercise training. Moreover, the positive clinical response to exercise is correlated with changes in skeletal muscle proteins involved in the regulation of mitochondrial biogenesis and metabolism. These changes in skeletal muscle gene expression offer a possible molecular explanation for the improvements in clinical outcomes.

  • 42. Ghaderi, Mehran
    et al.
    Gambelunghe, Giovanni
    Tortoioli, Cristina
    Brozzetti, Annalisa
    Jatta, Ken
    Örebro University, School of Health and Medical Sciences.
    Gharizadeh, Baback
    De Bellis, Annamaria
    Pecori Giraldi, Francesca
    Terzolo, Massimo
    Betterle, Corrado
    Falorni, Alberto
    MHC2TA single nucleotide polymorphism and genetic risk for autoimmune adrenal insufficiency2006In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 91, no 10, p. 4107-4111Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The polymorphism of class II HLA genes modulates the genetic risk for several endocrine autoimmune diseases. The constitutive class II expression on antigen-presenting cells is under the control of the MHC class II transactivator, encoded by the MHC2TA gene, which is mapped to chromosome 16p13. The MHC2TA -168 A-->G single nucleotide polymorphism (rs3087456) has been suggested to confer susceptibility to some autoimmune diseases. DESIGN: With the aim of testing whether this MHC2TA single nucleotide polymorphism is independently associated with autoimmune Addison's disease (AAD) and/or modulates the genetic risk conferred by DRB1-DQA1-DQB1 haplotypes, we analyzed DNA samples from 128 AAD patients and 406 healthy control subjects from continental Italy. RESULTS: Frequency of allele G of MHC2TA was significantly increased among AAD patients (39% alleles), compared with 29% in healthy controls (P = 0.003). Similarly, the frequency of AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a codominant (P = 0.012) and a G-dominant model (P = 0.018). Multivariate logistic regression analysis showed that MHC2TA AG+GG continued to be positively associated with genetic risk for AAD (P = 0.028, odds ratio = 1.72, 95% confidence interval = 1.06-2.78), after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04 (not 0403)-DQA1*0301-DQB1*0302 and DRB1*0403. Similar results were obtained when the number of G alleles was included in the model (P = 0.004; odds ratio = 1.65, 95% confidence interval = 1.17-2.32). CONCLUSIONS: Our study provides the first demonstration of the association of the polymorphism of the MHC2TA gene with genetic risk for AAD that appears to be independent from the well-known association with the polymorphism of HLA class II genes.

  • 43.
    Giesecke, Peter
    et al.
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Rosenqvist, Mårten
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Frykman, Viveka
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Friberg, Leif
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wallin, Göran
    Örebro University, School of Medical Sciences. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Höijer, Jonas
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lönn, Stefan
    Research and Development, Region Halland, Halmstad, Sweden.
    Törring, Ove
    Department of Clinical Research and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
    Increased Cardiovascular Mortality and Morbidity in Patients Treated for Toxic Nodular Goiter Compared to Graves' Disease and Nontoxic Goiter2017In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 27, no 7, p. 878-885Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous research has suggested an increased risk of death and cardiovascular disease in patients treated for hyperthyroidism. However, studies on this subject are heterogeneous, often based on old data, or have not considered the impact that treatment for hyperthyroidism might have on cardiovascular risk. It is also unclear whether long-term prognosis differs between Graves' disease and toxic nodular goiter. The aim of this study was to use a very large cohort built on recent data to assess whether improvements in cardiovascular care might have changed the prognosis over time. The study also investigated the impact of different etiologies of hyperthyroidism.

    METHODS: This was an observational register study for the period 1976-2012, with subjects followed for a median period of 18.4 years. Study patients were Stockholm residents treated for Graves' disease or toxic nodular goiter with either radioactive iodine or surgery (N = 12,239). This group was compared to Stockholm residents treated for nontoxic goiter (N = 3685), with adjustments made for age, sex, comorbidities, and time of treatment. Comparisons were also made to the general population of Stockholm. Outcomes were assessed in terms of all-cause and cardiovascular mortality as well as cardiovascular morbidity.

    RESULTS: The hazard ratios (HR) for all-cause mortality and for cardiovascular mortality were 1.27 [confidence interval (CI) 1.20-1.35] and 1.29 [CI 1.17-1.42], respectively, for hyperthyroid patients compared to those with nontoxic goiter. For cardiovascular morbidity, the HR was 1.12 [CI 1.06-1.18]. Patients aged ≥45 years who were treated for toxic nodular goiter were generally at greater risk than others, and those included from the year 1990 and onwards were at greater risk than those included earlier. Increased all-cause mortality, as well as cardiovascular mortality and morbidity, were also seen in comparisons with the general population.

    CONCLUSIONS: This is the first large study to indicate that the long-term risk of death and cardiovascular disease in hyperthyroid subjects is due to the hyperthyroidism itself and not an effect of confounding introduced by its treatment. Much of the excess risk is confined to individuals treated for toxic nodular goiter. Despite advances in cardiovascular care during recent decades, hyperthyroidism is still a diagnosis associated with increased cardiovascular morbidity and mortality.

  • 44.
    Gkourogianni, Alexandra
    et al.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stocholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Andrew, Melissa
    Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Tyzinski, Leah
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Crocker, Melissa
    Division of Endocrinology, Boston Children's Hospital, Boston MA, USA.
    Douglas, Jessica
    Division of Genetics, Boston Children's Hospital, Boston MA, USA.
    Dunbar, Nancy
    Division of Pediatric Endocrinology, Connecticut Children's Medical Center, Hartford CT, USA.
    Fairchild, Jan
    Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia.
    Funari, Mariana F. A.
    Unidade de Endocrinologia do Desenvolvimento (LIM/42), Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de Sao Paulo (USP), Sao Paulo, Brazil.
    Heath, Karen E.
    Institute of Medical & Molecular Genetics (INGEMM) and Skeletal dysplasia Multidisciplinary Unit (UMDE), Hospital La Paz Institute for Health Research (IdiPAZ), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Pediatrics, Hospital Universitario Infanta Sofia, Madrid, Spain.
    Jorge, Alexander A. L.
    Unidade de Endocrinologia do Desenvolvimento (LIM/42), Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de Sao Paulo (USP), Sao Paulo, Brazil.
    Kurtzman, Tracey
    El Rio Community Health Center, Tucson AZ, USA.
    LaFranchi, Stephen
    Department of Pediatrics, Oregon Health and Science University, Portland OR, USA.
    Lalani, Seema
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX, USA.
    Lebl, Jan
    Department of Pediatrics, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
    Lin, Yuezhen
    Pediatric Endocrinology and Metabolism, Baylor College of Medicine, Houston TX, USA.
    Los, Evan
    Department of Pediatrics, Oregon Health and Science University, Portland OR, USA.
    Newbern, Dorothee
    Division of Endocrinology, Phoenix Children's Hospital, Phoenix AZ, USA.
    Nowak, Catherine
    Division of Genetics, Boston Children's Hospital, Boston MA, USA.
    Olson, Micah
    Division of Endocrinology, Phoenix Children's Hospital, Phoenix AZ, USA.
    Popovic, Jadranka
    Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh PA, USA.
    Průhová, Štěpánka
    Department of Pediatrics, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
    Elblova, Lenka
    Department of Pediatrics, 2nd FacultDepartment of Pediatrics, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
    Quintos, Jose Bernardo
    Hasbro Children's Hospital, Providence RI, USA.
    Segerlund, Emma
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Sunderby Hospital, Sunderbyn, Sweden.
    Sentchordi, Lucia
    Institute of Medical & Molecular Genetics (INGEMM) and Skeletal dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Universidad Autónoma de Madrid, (IdiPAZ), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Pediatrics, Hospital Universitario Infanta Sofia, Madrid, Spain.
    Shinawi, Marwan
    Division of Genetics, Washington University, St. Louis MO, USA.
    Stattin, Eva-Lena
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Swartz, Jonathan
    Division of Endocrinology, Boston Children's Hospital, Boston MA, USA.
    Ariadna, González-Del Angel
    Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City, México.
    Sinhué, Díaz-Cuéllar
    Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes-Cuicuilco, Coyoacán, México.
    Hosono, Hidekazu
    Cottage Children's Medical Center, Santa Barbara CA, USA.
    Sanchez-Lara, Pedro A.
    Center for Personalized Medicine, Children's Hospital of Los Angeles, Los Angeles CA, USA.
    Hwa, Vivian
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Baron, Jeffrey
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA; Örebro University Hospital, Örebro, Sweden.
    Dauber, Andrew
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 460-469Article in journal (Refereed)
    Abstract [en]

    Context: Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, premature growth cessation and minor skeletal abnormalities.

    Objective: Characterize the phenotypic spectrum, associated conditions and response to growth-promoting therapies.

    Design: Retrospective international cohort study.

    Patients: Information from 103 individuals (57 female, 46 male) from 20 families with confirmed heterozygous ACAN mutations were included.

    Methods: Families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next generation sequencing, and/or Sanger sequencing. Clinical information was collected from medical records.

    Results: Identified ACAN variants showed perfect co-segregation with phenotype. Adult individuals had mildly disproportionate short stature (median height: -2.8 SDS, range: -5.9 to -0.9) and histories of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). There was no apparent genotype-phenotype correlation between type of ACAN mutation and presence of joint complaints. During childhood, height was less affected (median height: -2.0 SDS, range: -4.2 to -0.6). In contrast to most children with short stature, the majority of children had advanced BA (BA - CA, median: +1.3y; range +0.0 to +3.7y) reflecting a reduction in remaining growth potential. Nineteen individuals had received GH with some evidence of increased growth velocity.

    Conclusions Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. In several of the families, affected individuals developed early-onset osteoarthritis and degenerative disc disease requiring intervention, suggesting dysfunction of articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

  • 45.
    Gkourogianni, Alexandra
    et al.
    Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Segerlund, Emma
    Sunderby Hospital, Sunderbyn, Sweden.
    Hallgrimsdottir, Sigrun
    Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Stattin, Eva-Lena
    Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 424-424Article in journal (Other academic)
    Abstract [en]

    Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.

    Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (3shoulders, 10hands, 10wrists, 17spines, 10pelvis, 31hips, 79knees, 5 lower-legs, 4ankles, 4feet).Furthermore 2 computed tomography scans (1hip; 1knee), and 5 magnetic resonance scans (2hips; 3knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.

    Results: In the group of children (n=6; age ≤15yo; 3F:3M), six had moderately advanced BA (range:6-17.5months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also present-ed OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy.Among 16 adult patients (5F:11M), 16 had OCD (7elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40y) OA, (1shoulder, 5elbows, 3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs.Moreover 8 adult patients (3F:5M) have been operated, 4 pa-tients had hip replacement (1F:3M;3bilateral;1unilateral) and 5 knee arthroplasties (2F:3M; 3bilateral;2unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand x-rays and found no brachydactyly.

    Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height

  • 46.
    González-Gil, E. M.
    et al.
    GENUD (Growth, Exercise, Nutrition and Development) Research Group, University of Zaragoza, Zaragoza, Spain; Faculty of Health Sciences, University of Zaragoza, Zaragoza, Spain.
    Mouratidou, T.
    GENUD (Growth, Exercise, Nutrition and Development) Research Group, University of Zaragoza, Zaragoza, Spain.
    Cardon, G.
    Department of Movement and Sport Sciences, Ghent University, Ghent, Belgium.
    Androutsos, O.
    Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
    De Bourdeaudhuij, I.
    Department of Movement and Sport Sciences, Ghent University, Ghent, Belgium.
    Góźdź, M.
    The Children’s Memorial Health Institute, Warsaw, Poland.
    Usheva, N.
    Department of Social Medicine and Health Care Organization, Medical University Varna, Varna, Bulgaria.
    Birnbaum, J.
    Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University of Munich, München, Germany.
    Manios, Y.
    Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
    Moreno, L. A.
    GENUD (Growth, Exercise, Nutrition and Development) Research Group, University of Zaragoza, Zaragoza, Spain; Faculty of Health Sciences, University of Zaragoza, Zaragoza, Spain.
    Nilsen, Bente (Contributor)
    Oslo and Akershus University College of Applied Science, Oslo, Norway.
    Reliability of primary caregivers reports on lifestyle behaviours of European pre-school children: the ToyBox-study2014In: Obesity Reviews, ISSN 1467-7881, E-ISSN 1467-789X, Vol. 15, no Suppl 3, p. 61-66Article in journal (Refereed)
    Abstract [en]

    Reliable assessments of health-related behaviours are necessary for accurate evaluation on the efficiency of public health interventions. The aim of the current study was to examine the reliability of a self-administered primary caregivers questionnaire (PCQ) used in the ToyBox-intervention. The questionnaire consisted of six sections addressing sociodemographic and perinatal factors, water and beverages consumption, physical activity, snacking and sedentary behaviours. Parents/caregivers from six countries (Belgium, Bulgaria, Germany, Greece, Poland and Spain) were asked to complete the questionnaire twice within a 2-week interval. A total of 93 questionnaires were collected. Test-retest reliability was assessed using intra-class correlation coefficient (ICC). Reliability of the six questionnaire sections was assessed. A stronger agreement was observed in the questions addressing sociodemographic and perinatal factors as opposed to questions addressing behaviours. Findings showed that 92% of the ToyBox PCQ had a moderate-to-excellent test-retest reliability (defined as ICC values from 0.41 to 1) and less than 8% poor test-retest reliability (ICC < 0.40). Out of the total ICC values, 67% showed good-to-excellent reliability (ICC from 0.61 to 1). We conclude that the PCQ is a reliable tool to assess sociodemographic characteristics, perinatal factors and lifestyle behaviours of pre-school children and their families participating in the ToyBox-intervention.

  • 47.
    Goodyear, Laurie J.L
    et al.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States; Metabolism Section, Joslin Diabetes Center, One Joslin Place, Boston MA, United States.
    Hershman, Michael F.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Napoli, Raffaele
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Calles, Jorge
    Division of Endocrinology, Department of Medicine, University of Vermont, Burlington VT, United States.
    Markuns, Jeffrey F.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Ljungqvist, Olle
    Örebro University, School of Medical Sciences. Department of Surgery, Karolinska Hospital and Institute, Stockholm, Sweden.
    Horton, Edward S.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Glucoseingestion causes GLUT4 translocation in human skeletal muscle1996In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 45, no 8, p. 1051-1056Article in journal (Refereed)
    Abstract [en]

    In humans, ingestion of carbohydrates causes an increase in blood glucose concentration, pancreatic insulin release, and increased glucose disposal into skeletal muscle. The underlying molecular mechanism for the increase in glucose disposal in human skeletal muscle after carbohydrate ingestion is not known. We determined whether glucoseingestion increases glucose uptake in human skeletal muscle by increasing the number of glucose transporter proteins at the cell surface and/or by increasing the activity of the glucose transporter proteins in the plasma membrane. Under local anesthesia, approximately 1 g of vastus lateralis muscle was obtained from six healthy subjects before and 60 min after ingestion of a 75-g glucose load. Plasma membranes were isolated from the skeletal muscle and used to measure GLUT4 and GLUT1 content and glucosetransport in plasma membrane vesicles. Glucose ingestion increased the plasma membrane content of GLUT4 per gram muscle (3,524 +/- 729 vs. 4,473 +/- 952 arbitrary units for basal and 60 min, respectively; P < 0.005). Transporter-mediated glucosetransport into plasma membrane vesicles was also significantly increased (130 +/- 11 vs. 224 +/- 38 pmol.mg-1.s-1; P < 0.017), whereas the calculated ratio of glucose transport to GLUT4, an indication of transporter functional activity, was not significantly increased 60 min after glucose ingestion (2.3 +/- 0.4 vs. 3.0 +/- 0.5 pmol.GLUT4 arbitrary units-1.s-1; P < 0.17). These results demonstrate that oral ingestion of glucose increases the rate of glucose transport across the plasma membrane and causes GLUT4 translocation in human skeletal muscle. These findings suggest that under physiological conditions the translocation of GLUT4 is an important mechanism for the stimulation of glucose uptake in human skeletal muscle.

  • 48.
    Greiner, Thomas U.
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    The gut microbiota modulates glycaemic control and serum metabolite profiles in non-obese diabetic mice2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e110359Article in journal (Refereed)
    Abstract [en]

    Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses.

  • 49.
    Hildén, Karin
    et al.
    Örebro University, School of Medical Sciences.
    Arntyr-Hellgren, Paulina
    Magnuson, Anders
    Hanson, Ulf
    Simmons, David
    Örebro University, School of Medical Sciences.
    Fadl, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Born over 4500 g: the trends in birth trauma and mode of delivery in women with GDM and type 1 diabetes in Sweden between 1998-20122018Conference paper (Refereed)
    Abstract [en]

    Background: We have previously shown that during the years 1998-2012, the overall incidence of LGA and birthweight decreased in both women with and without GDM in Sweden, and unpublished preliminary results show that there is a converse trend among women with T1DM. The incidence of Erbs palsy also decreased in the GDM and background population, but remained unchanged for women with T1DM. Since macrosomia is one of the most prominent risk factors for Erb´s palsy and delivery complications, the aim of the study was to evaluate trends in incidence of Erb´s palsy and delivery mode in the macrosomic group defined as weight ≥4500g and we present here our preliminary results.

    Method: This is a cohort study in Sweden 1998-2012 , including singleton macrosomic (≥4500 g) births. Vaginal deliveries were selected for the analyses relating to Erb´s plasy. Poisson regression was used to evaluate trends per year in both the GDM, T1DM and the background population. Results were partly stratified on BMI, to be able to detect any group differences in trends. P-value of <0.05 was considered statistically significant.

    Results: In total there were 57 2015 macrosomic infants, of whom (n= 36 933, 64,6%) were delivered vaginally. Of these, only 2.1 % (n=798) were vaginally delivered by women with GDM, (1.4%) type 2 diabetes (0.1%) or T1DM (0.7%). The trend in Erb´s palsy decreased significantly in the background population at a rate of OR 0.954 (95% CI 0.936-0.973) per year. For women with GDM or T1DM there was no significant change in incidence of trends over these years for Erb´s palsy. As for Caesarean section (CS) there was a significant increase per year for GDM pregnancies (OR 1.028, 95% CI 1.007-1.049) and in the background population (1.018 95% CI 1.013-1.022). No change was seen for CS in pregnancies with T1DM.

    Conclusion: Even though the rates of LGA and birthweight have decreased in Sweden over this time period for women with GDM and the background population, we could not see a significant decrease in Erb´s palsy among women with vaginal births in either the GDM group or for women with T1DM in the macrosomic infants. However, a decrease was seen in the incidence of Erb´s palsy in the macrosomic babies in the background population. The rates of CS have significantly increased in the background population and for GDM pregnancies, but been stable for T1DM. We conclude that the disparity in risk of Erbs has grown over this time period. Further work is needed to ascertain whether this is due to the need for improved surveillance, a higher CS rate, and/or improved glycaemic management (or other factors).

  • 50.
    Hildén, Karin
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology.
    Hanson, Ulf
    Örebro University, School of Health Sciences. DeDepartment of Obstetrics and Gynaecology, School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Persson, M.
    Department of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Fadl, Helena
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology.
    Overweight and obesity: a remaining problem in women treated for severe gestational diabetes2016In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 33, no 8, p. 1045-1051Article in journal (Refereed)
    Abstract [en]

    Aim: To analyse the impact of overweight and obesity on the risk of adverse maternal outcomes and fetal macrosomia in pregnancies of women treated for severe gestational diabetes.

    Methods This was a population-based cohort study including all singleton pregnancies in Sweden without pre-existing diabetes in the period 1998-2012. Only mothers with an early- pregnancy BMI of ≥18.5 kg/m² were included. Logistic regression analysis was used to determine odds ratios with 95% CIs for maternal outcomes and fetal growth. Analyses were stratified by maternal gestational diabetes/non-gestational diabetes to investigate the impact of overweight/obesity in each group.

    Results: Of 1 249 908 singleton births, 13 057 were diagnosed with gestational diabetes (1.0%). Overweight/obesity had the same impact on the risks of caesarean section and fetal macrosomia in pregnancies with and without gestational diabetes, but the impact of maternal BMI on the risk of preeclampsia was less pronounced in women with gestational diabetes. Normal-weight women with gestational diabetes had an increased risk of caesarean section [odds ratio 1.26 (95% CI 1.16-1.37)], preeclampsia [odds ratio 2.03 (95% CI 1.71-2.41)] and large-for-gestational-age infants [odds ratio 2.25 (95% CI 2.06-2.46)]. Risks were similar in the overweight group without gestational diabetes, caesarean section [odds ratio 1.34 (1.33-1.36)], preeclampsia odds ratio [1.76 (95% CI 1.72-1.81)], large-for-gestational-age [odds ratio 1.76 (95% CI 1.74-1.79)].

    Conclusions: Maternal overweight and obesity is associated with similar increments in risks of adverse maternal outcomes and delivery of large-for-gestational-age infants in women with and without gestational diabetes. Obese women with gestational diabetes are defined as a high-risk group. Normal-weight women with gestational diabetes have similar risks of adverse outcomes to overweight women without gestational diabetes.

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