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  • 1. Bjursell, Magnus K.
    et al.
    Blom, Henk J.
    Cayuela, Jordi Asin
    Engvall, Martin L.
    Lesko, Nicole
    Balasubramaniam, Shanti
    Brandberg, Goran
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Falkenberg, Maria
    Jakobs, Cornelis
    Smith, Desiree
    Struys, Eduard
    von Dobeln, Ulrika
    Gustafsson, Claes M.
    Lundeberg, Joakim
    Wedell, Anna
    Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 89, no 4, p. 507-515Article in journal (Refereed)
    Abstract [en]

    Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (Ado Met), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.

  • 2. Bozzola, Mauro
    et al.
    Colle, Michel
    Halldin-Stenlid, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Larroque, Sylvain
    Zignani, Monia
    Treatment adherence with the easypod (TM) growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents2011In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 11, p. 4-Article in journal (Refereed)
    Abstract [en]

    Background: Accurately monitoring adherence to treatment with recombinant human growth hormone (r-hGH) enables appropriate intervention in cases of poor adherence. The electronic r-hGH auto-injector, easypod(TM), automatically records the patient's adherence to treatment. This study evaluated adherence to treatment of children who started using the auto-injector and assessed opinions about the device. Methods: A multicentre, multinational, observational 3-month survey in which children received r-hGH as part of their normal care. Physicians reviewed the recorded dose history and children (with or without parental assistance) completed a questionnaire-based survey. Children missing <= 2 injections per month (92% of injections given) were considered adherent to treatment. Adherence was compared between GH treatment-naive and treatment-experienced children. Results: Of 834 recruited participants, 824 were evaluated. The median (range) age was 11 (1-18) years. From the recorded dose history, 87.5% of children were adherent to treatment over the 3-month period. Recorded adherence was higher in treatment-naive (89.7%, n = 445/496) than in treatment-experienced children (81.7%, n = 152/186) [Fisher's exact test FI(X) = 7.577; p = 0.0062]. According to self-reported data, 90.2% (607/673) of children were adherent over 3 months; 51.5% (421/817) missed >= 1 injection over this period (mainly due to forgetfulness). Concordance between reported and recorded adherence was 84.3%, with a trend towards self-reported adherence being higher than recorded adherence. Most children liked the auto-injector: over 80% gave the top two responses from five options for ease of use (720/779), speed (684/805) and comfort (716/804). Although 38.5% (300/780) of children reported pain on injection, over half of children (210/363) considered the pain to be less or much less than expected. Given the choice, 91.8% (732/797) of children/parents would continue using the device. Conclusions: easypod(TM) provides an accurate method of monitoring adherence to treatment with r-hGH. In children who received treatment with r-hGH using easypod(TM), short-term adherence is good, and significantly higher in treatment-naive children compared with experienced children. Children/parents rate the device highly. The high level of acceptability of the device is reflected by a desire to continue using it by over 90% of the children in the survey.

  • 3. Chaplin, John E.
    et al.
    Kriström, Berit
    Jonsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Halldin Stenlid, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Aronson, A. Stefan
    Dahlgren, Jovanna
    Albertsson-Wikland, Kerstin
    When Do Short Children Realize They Are Short?: Prepubertal Short Children's Perception of Height during 24 Months of Catch-Up Growth Hormone Treatment2012In: Hormone Research in Paediatrics, ISSN 1663-2818, Vol. 77, no 4, p. 241-249Article in journal (Refereed)
    Abstract [en]

    Aim: To examine perceived height during the first 24 months of growth hormone (GH) treatment in short prepubertal children. Methods: Ninety-nine 3- to 11-year-old short prepubertal children with either isolated GH deficiency (n = 32) or idiopathic short stature (n = 67) participated in a 24-month randomized trial of individualized or fixed-dose GH treatment. Children's and parents' responses to three perceived height measures: relative height (Silhouette Apperception Test), sense of height (VAS short/tall), and judgment of appropriate height (yes/no) were compared to measured height. Results: Children and parents overestimated height at start (72%, 54%) and at 24 months (52%, 30%). Short children described themselves as tall until 8.2 years (girls) and 9 years (boys). Prior to treatment, 38% of children described their height as appropriate and at 3 months, 63%. Mother's height, parental sense of the child's tallness and age explained more variance in children's sense of tallness (34%) than measured height (0%). Conclusion: Short children and parents overestimate height; a pivotal age exists for comparative height judgments. Even a small gain in height may be enough for the child to feel an appropriate age-related height has been reached and to no longer feel short. 

  • 4.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Nordling Eriksson, Gabriel
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Hallgren, Åsa
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Wahlberg, Jeanette
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Fac Hlth Sci, SE-58183 Linkoping, Sweden.
    Ekwall, Olov
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olcén, Per
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Winqvist, Ola
    Karolinska Inst, Karolinska Univ Hosp, Translat Immunol, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Kriström, Berit
    Umea Univ, Inst Clin Sci, Pediat, SE-90736 Umea, Sweden.
    Laudius, Maria
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Halldin Stenlid, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gebre-Medhin, Gennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Björnsdottir, Sigridur
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Janson, Annika
    Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.
    Åkerman, Anna-Karin
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Åman, Jan
    Univ Orebro, Dept Pediat, Fac Med & Hlth, SE-70281 Orebro, Sweden.
    Duchen, Karel
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Bergthorsdottir, Ragnhildur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Lindskog, Emma
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, SE-40530 Gothenburg, Sweden.
    Landin-Olsson, Mona
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Elfving, Maria
    Lund Univ, Dept Pediat, Pediat Endocrinol, Clin Sci, SE-22362 Lund, Sweden.
    Waldenström, Erik
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 379-389Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 5. Decker, Ralph
    et al.
    Albertsson-Wikland, Kerstin
    Kristrom, Berit
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Dahlgren, Jovanna
    Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 3, p. 407-415Article in journal (Refereed)
    Abstract [en]

    Objective Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period.

    Design Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17100 mu g/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental heightSDS, children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n=28) or an unchanged individualized dose (UID, n=37) for 2years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43 mu g/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX.

    Results We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homoeostasis model assessment (-55.1%), lean soft tissue (-27.8%) and bone mineral content (-31.3%) in RID compared with UID (all P<0.05), but no differences compared with FIX.

    Conclusions Continued reduced individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired heightSDS is achieved to avoid overtreatment in terms of metabolic outcome.

  • 6.
    Fahnehjelm, Kristina Tear
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;St Erik Eye Hosp, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Akad, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Liu, Ying
    Karolinska Univ Hosp, Dept Clin Neurophysiol, Huddinge, Sweden.;Soder Sjukhuset, Dept Ophthalmol, Stockholm, Sweden..
    Olsson, David
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Paediat, Stockholm, Sweden..
    Amren, Urban
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;St Erik Eye Hosp, Stockholm, Sweden..
    Haglind, Charlotte Bieneck
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Paediat, Stockholm, Sweden..
    Holmström, Gerd
    Univ Uppsala Hosp, Dept Neurosci Ophthalmol, Uppsala, Sweden..
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Andreasson, Sten
    Lund Univ, Dept Ophthalmol, Lund, Sweden..
    Nordenstrom, Anna
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Paediat, Stockholm, Sweden..
    Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function2016In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 12, p. 1451-1460Article in journal (Refereed)
    Abstract [en]

    Aim: There have been few studies on long-term electroretinographic findings in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). This study correlated long-term electroretinographic findings with age, metabolic control and clinical symptoms. Methods: We examined 12 Swedish patients with LCHADD. Visual acuity testing, fundus examinations, optical coherence tomography and electroretinography were performed. The results were correlated to age, the levels of 3-hydroxyacylcarnitine and acylcarnitine and clinical metabolic control. Results: Blindness or moderate visual impairment was found in two patients. Retinal pigmentation, atrophy and fibrosis were present in 11, seven and one of the patients, respectively, and optical coherence tomography showed retinal thinning in three of the six patients examined. Electroretinography was performed on 11 of the 12 patients. It was pathological, with reduced rod and cone responses, in five patients, subnormal in four and was related to poor clinical metabolic control and severe neonatal symptoms. Repeated electroretinographies revealed reduced function with increasing age. Conclusion: More than 80% of the LCHADD patients developed pathological or subnormal retinal function. This was more pronounced in patients with neonatal symptoms, but ameliorated by strict dietary treatment. Annual ophthalmological follow-ups, with electroretinography every second or third year, are recommended.

  • 7.
    Haglind, C Bieneck
    et al.
    Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden.
    Nordenström, A
    Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden.
    Ask, S
    Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    von Döbeln, U
    Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Stenlid, Maria Halldin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Increased and early lipolysis in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency during fast2015In: Journal of Inherited Metabolic Disease, ISSN 0141-8955, E-ISSN 1573-2665, Vol. 38, no 2, p. 315-322Article in journal (Refereed)
    Abstract [en]

    Children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) have a defect in the degradation of long-chain fatty acids and are at risk of hypoketotic hypoglycemia and insufficient energy production as well as accumulation of toxic fatty acid intermediates. Knowledge on substrate metabolism in children with LCHAD deficiency during fasting is limited. Treatment guidelines differ between centers, both as far as length of fasting periods and need for night feeds are concerned. To increase the understanding of fasting intolerance and improve treatment recommendations, children with LCHAD deficiency were investigated with stable isotope technique, microdialysis, and indirect calometry, in order to assess lipolysis and glucose production during 6 h of fasting. We found an early and increased lipolysis and accumulation of long chain acylcarnitines after 4 h of fasting, albeit no patients developed hypoglycemia. The rate of glycerol production, reflecting lipolysis, averaged 7.7 ± 1.6 µmol/kg/min, which is higher compared to that of peers. The rate of glucose production was normal for age; 19.6 ± 3.4 µmol/kg/min (3.5 ± 0.6 mg/kg/min). Resting energy expenditure was also normal, even though the respiratory quotient was increased indicating mainly glucose oxidation. The results show that lipolysis and accumulation of long chain acylcarnitines occurs before hypoglycemia in fasting children with LCHAD, which may indicate more limited fasting tolerance than previously suggested.

  • 8. Haglind, Charlotte Bieneck
    et al.
    Ask, Sara
    von Dobeln, Ulrika
    Engvall, Martin
    Ekblom, Orjan
    Stenlid, Maria Halldin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordenström, Anna
    Energy expenditure and lipid metabolism in very long-chain Acyl-CoA dehydrogenase (VLCAD) deficiency2015In: Molecular Genetics and Metabolism, ISSN 1096-7192, E-ISSN 1096-7206, Vol. 114, no 3, p. 333-333Article in journal (Other academic)
  • 9.
    Katsu-Jimenez, Yurika
    et al.
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Vazquez-Calvo, Carmela
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Maffezzini, Camilla
    Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Peng, Xiaoxiao
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Coastal Int Holdings Ltd, Strateg Investment Dept, Shenzhen, Peoples R China.
    Freyer, Christoph
    Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Wredenberg, Anna
    Karolinska Inst, Div Mol Metab, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Gimenez-Cassina, Alfredo
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden;Univ Autonoma Madrid, Dept Mol Biol, Ctr Biol Mol Severo Ochoa, Madrid, Spain.
    Wedell, Anna
    Karolinska Inst, Dept Mol Med & Surg, Sci Life Lab, Stockholm, Sweden;Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden.
    Arner, Elias S. J.
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate2019In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 4, p. 709-723Article in journal (Refereed)
    Abstract [en]

    Thioredoxin-interacting protein (TXNIP) is an -arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes -cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.

  • 10.
    Stenlid, Maria Halldin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ahlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Forslund, Anders H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Döblen, U v
    Nordström, A
    Brown, RM
    Eklund, C
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Glucose Production, Lipolysis and Energy Expenditure in an Infantwith Deficiency of the Pyruvate Dehydrogenase Complex2014In: Journal of Pediatric Endocrinology & Metabolism (JPEM), ISSN 0334-018X, E-ISSN 2191-0251Article in journal (Refereed)
  • 11.
    Stenlid, Maria Halldin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Ahlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Forslund, Anders H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    von Döbeln, Ulrika
    Centre for Inherited Metabolic Disease, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Energy substrate metabolism in pyruvate dehydrogenase complex deficiency2014In: Journal of Pediatric Endocrinology & Metabolism (JPEM), ISSN 0334-018X, E-ISSN 2191-0251, Vol. 27, no 11-12, p. 1059-1064Article in journal (Refereed)
    Abstract [en]

    Pyruvate dehydrogenase (PDH) deficiency is an inherited disorder of carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. In order to provide energy for the brain, a ketogenic diet has been tried. Both the disorder and the ketogenic therapy may influence energy production. The aim of the study was to assess hepatic glucose production, lipolysis and resting energy expenditure (REE) in an infant, given a ketogenic diet due to neonatal onset of the disease. Lipolysis and glucose production were determined for two consecutive time periods by constant-rate infusions of [1,1,2,3,3-2H5]-glycerol and [6,6-2H2]-glucose. The boy had been fasting for 2.5 h at the start of the sampling periods. REE was estimated by indirect calorimetry. Rates of glucose production and lipolysis were increased compared with those of term neonates. REE corresponded to 60% of normal values. Respiratory quotient (RQ) was increased, indicating a predominance of glucose oxidation. Blood lactate was within the normal range. Several mechanisms may underlie the increased rates of glucose production and lipolysis. A ketogenic diet will result in a low insulin secretion and reduced peripheral and hepatic insulin sensitivity, leading to increased production of glucose and decreased peripheral glucose uptake. Surprisingly, RQ was high, indicating active glucose oxidation, which may reflect a residual enzyme activity, sufficient during rest. Considering this, a strict ketogenic diet might not be the optimal choice for patients with PDH deficiency. We propose an individualised diet for this group of patients aiming at the highest glucose intake that each patient will tolerate without elevated lactate levels.

  • 12.
    Stenlid, Rasmus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Med, SE-43183 Molndal, Sweden.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Med, SE-43183 Molndal, Sweden.
    Manukyan, Levon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weghuber, D
    Paulmichl, K
    Zsoldos, F
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    High DPP-4 concentrations in adolescents are associated with low intact GLP-12018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 8, p. 2958-2966Article in journal (Refereed)
    Abstract [en]

    Context: Dipeptidyl Peptidase-4 (DPP-4) metabolizes glucagon-like peptide-1 (GLP-1) and increased DPP4 levels are associated with obesity and visceral adiposity in adults.

    Objective: Investigating DPP-4 levels in adolescents and association with, firstly, circulating intact GLP-1 levels and glucose tolerance, secondly, BMI, and, thirdly visceral, subcutaneous and liver fat compartments.

    Design: Cross-sectional study, July 2012 to April 2015.

    Setting: Pediatric obesity clinic, Uppsala University Hospital.

    Patients and participants: Children and adolescents with obesity (n=59) and lean controls (n=21), age 8-18.

    Main outcome measures: BMI SDS, fasting plasma concentrations of DPP-4, total and intact GLP-1, fasting and OGTT concentrations of glucose and visceral (VAT) and subcutaneous (SAT) adipose tissue volumes and liver fat fraction.

    Results: Plasma DPP-4 decreased with age both in obese (41 ng/ml per year) and lean subjects (48 ng/ml per year). Plasma DPP-4 was higher in males both in the obesity and lean group. When adjusting for age and sex, plasma DPP-4 was negatively associated with intact GLP-1 at fasting, B=-12.3, 95% CI [-22.9, -1.8] and during OGTT, B=-12.1, 95% CI [-22.5, -1.7]. No associations were found between DPP-4 and plasma glucose measured at fasting or after a 2-hour OGTT. Plasma DPP-4 was 19% higher in the obese subjects. Among adipose tissue compartments the strongest association was with VAT, B=0.05, 95% CI [-0.02, 0.12].

    Conclusions: In adolescents, high plasma DPP-4 concentrations are associated with low proportion of intact GLP-1, high BMI, young age and male sex. The observed associations are compatible with an increased metabolism of GLP-1 in childhood obesity.

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