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  • 1. 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. 

  • 2.
    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.

  • 3.
    Bergens, Oscar
    et al.
    Örebro University, School of Health Sciences.
    Nilsson, Andreas
    Örebro University, School of Health Sciences.
    Kadi, Fawzi
    Örebro University, School of Health Sciences.
    Cardiorespiratory Fitness Does Not Offset Adiposity-Related Systemic Inflammation in Physically Active Older Women2019In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 9, p. 4119-4126Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Chronic inflammation increases diabetes risk and may be exacerbated by excess adipose tissue. Whether cardiovascular fitness can offset chronic inflammation associated with excess adipose tissue in older adults is unclear.

    OBJECTIVE: The study aimed to examine the influence of cardiorespiratory fitness on links between adiposity and pro- and anti-inflammatory biomarkers related to metabolic risk in physically active older women.

    DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study comprising older community-dwelling women (n = 109; age, 65-70 yr).

    MAIN OUTCOME: Cardiorespiratory fitness was assessed using a standardized submaximal test and participants were categorized into high and low adiposity-related metabolic risk (body mass index, waist-to-hip ratio (WHR) and total fat mass). The inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, IL-18, adiponectin, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP-1α) were analyzed.

    RESULTS: Regardless of adiposity measure, women in the metabolic high-risk group had significantly (P<0.05) elevated CRP and lower adiponectin levels. Levels of IL-6 and MIP1-α were significantly elevated in the high-risk group defined by WHR and total fat mass. IL-18 level was significantly elevated in the high-risk group based on WHR only. Importantly, a high cardiorespiratory fitness level did not attenuate the detrimental links between adiposity measures and inflammation.

    CONCLUSIONS: Altogether, cardiorespiratory fitness does not offset the detrimental links between adiposity and several inflammatory biomarkers related to metabolic risk in physically active older women. Reducing abdominal adipose tissue in older adults should be emphasized in efforts aiming to attenuate age-related systemic inflammation and metabolic risk regardless of cardiorespiratory fitness.

  • 4.
    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.

  • 5.
    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.

  • 6.
    Ekelund, Ulf
    et al.
    Örebro University, School of Health and Medical Sciences.
    Ong, Ken K.
    Linné, Yvonne
    Neovius, Martin
    Brage, Sören
    Dunger, David B.
    Wareham, Nicholas J.
    Rössner, Stephan
    Association of weight gain in infancy and early childhood with metabolic risk in young adults2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 1, p. 98-103Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Early postnatal life has been suggested as an important window during which risks for long-term health may be influenced. OBJECTIVE: The aim of this study was to examine the independent associations between weight gain during infancy (0-6 months) and early childhood (3-6 yr) with components of the metabolic syndrome in young adults. DESIGN: This was a prospective cohort study (The Stockholm Weight Development Study). SETTING: The study was conducted in a general community. PARTICIPANTS: Subjects included 128 (54 males) singletons, followed from birth to 17 yr. MAIN OUTCOME MEASURE: None of these young adults met the full criteria for the metabolic syndrome. We therefore calculated a continuous clustered metabolic risk score by averaging the standardized values of the following components: waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, glucose, and insulin level. RESULTS: Clustered metabolic risk at age 17 yr was predicted by weight gain during infancy (standardized beta = 0.16; P < 0.0001) but not during early childhood (standardized beta = 0.10; P = 0.23), adjusted for birth weight, gestational age, current height, maternal fat mass, and socioeconomic status at age 17 yr. Further adjustment for current fat mass and weight gain during childhood did not alter the significant association between infancy weight gain with the metabolic risk score (standardized beta = 0.20; P = 0.007). CONCLUSIONS: Rapid weight gain during infancy (0-6 months) but not during early childhood (3-6 yr) predicted clustered metabolic risk at age 17 yr. Early interventions to moderate rapid weight gain even at very young ages may help to reduce adult cardiovascular disease risks.

  • 7.
    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.

  • 8.
    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.

  • 9.
    Fadini, Gian Paolo
    et al.
    Department of Medicine, Division of Metabolic Diseases, University of Padova, Padova, Italy.
    Feher, Michael
    Beta Cell Diabetes Centre, Chelsea and Westminster Hospital, London, UK; Department of Clinical and Experimental Medicine, University of Surrey, Guilford, UK.
    Hansen, Troels Krarup
    Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
    de Valk, Harold W.
    Department of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
    Koefoed, Mette Marie
    Novo Nordisk A/S, Søborg, Denmark.
    Wolden, Michael
    Novo Nordisk A/S, Søborg, Denmark.
    Zimmerman, E.
    Novo Nordisk A/S, Søborg, Denmark.
    Jendle, Johan
    Örebro University, School of Medical Sciences.
    Switching to Degludec from Other Basal Insulins is Associated with Reduced Hypoglycemia Rates: a Prospective Study2019In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 12, p. 5977-5990Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Observational studies of insulin degludec (degludec) with hypoglycemia events prospectively recorded are lacking.

    OBJECTIVE: To evaluate the safety and effectiveness of degludec in patients with type 1 (T1D) or type 2 diabetes (T2D) switching from other basal insulins in routine care.

    DESIGN: ReFLeCT was a multinational, multicenter, prospective, observational, single-arm study comprising a 4-week baseline period (pre-switch basal insulin) and 12-month follow-up (degludec).

    SETTING: Routine clinical practice. Patients or Other Participants: Insulin-treated patients (≥18 years) with T1D (n=556) or T2D (n=611) with treatment plans to initiate degludec.

    INTERVENTIONS: Switching to degludec from other basal insulins.

    MAIN OUTCOME MEASURE(S): Change from baseline in number of overall hypoglycemic events recorded in patient diaries.

    RESULTS: In T1D, the 12-month follow-up/baseline rate ratios [95% CI] of overall (0.80 [0.74;0.88]), non-severe (0.83 [0.76;0.91]), severe (0.28 [0.14;0.56]) and nocturnal (0.61 [0.50;0.73]) hypoglycemia suggested significantly reduced hypoglycemia rates with degludec (all P<0.001). At 12 months, HbA1c, fasting plasma glucose (FPG) and basal insulin dose decreased significantly. Body weight increased and treatment satisfaction improved significantly. In T2D, the hypoglycemia rate ratios were: overall (0.46 [0.38;0.56]), non-severe (0.53 [0.44;0.64]) and nocturnal (0.35 [0.20;0.62]) (all P<0.001; too few events for analysis of severe). At 12 months, HbA1c and FPG decreased significantly. Body weight and insulin doses remained unchanged, and treatment satisfaction was significantly improved.

    CONCLUSIONS: In a routine clinical care setting, switching to degludec from other basal insulins was associated with significantly reduced rates of hypoglycemia, improved glycemic control, and treatment satisfaction in patients with T1D or T2D.

  • 10.
    Gauthier, Marie-Soleil
    et al.
    Institut de Recherches Cliniques de Montréal, Montréal QC, Canada; Montreal Diabetes Research Centre, Centre de Recherche du Centre Hospitalier de L'Université de Montréal (CRCHUM), Montréal QC, Canada.
    Rabasa-Lhoret, Remi
    Institut de Recherches Cliniques de Montréal, Montréal QC, Canada; Montreal Diabetes Research Centre, Centre de Recherche du Centre Hospitalier de L'Université de Montréal (CRCHUM), Montréal QC, Canada; Nutrition Department, Université de Montréal, Montréal, Canada; Endocrinology Division, Montreal University Hospital, Montréal QC, Canada; School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa ON, Canada.
    Prud'homme, Denis
    Institut de Recherche de L'Hôpital Montfort, Ottawa ON, Canada .
    Karelis, Antony D.
    Department of Kinanthropology, Université du Québec À Montréal, Montréal QC, Canada .
    Geng, Dawei
    Örebro University, School of Science and Technology.
    van Bavel, Bert
    Örebro University, School of Science and Technology.
    Ruzzin, Jeorme
    Department of Biology, University of Bergen, Bergen, Norway.
    The Metabolically Healthy But Obese Phenotype Is Associated With Lower Plasma Levels of Persistent Organic Pollutants as Compared to the Metabolically Abnormal Obese Phenotype2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 6, p. E1061-E1066Article in journal (Refereed)
    Abstract [en]

    Context: Although obesity is strongly linked to insulin resistance and type 2 diabetes, a subset of obese individuals termed metabolically healthy but obese(MHO) appears relatively protected from the development of cardiometabolic complications. The origins of this metabolically healthy phenotype remain unclear. Recently, persistent organic pollutants (POPs) have emerged as potential endocrine disruptors.

    Objective: The aim of this study was to test the hypothesis that the MHO phenotype presents lower circulating levels of POPs as compared to the metabolically abnormal obese (MAO) phenotype.

    Design, Setting, and Patients: We conducted a cross-sectional study of 76 nondiabetic obese (body mass index >= 30 kg/m(2)) postmenopausal women.

    Main Outcome Measures: Plasma concentrations of 21 POPs as well as cardiometabolic risk factors were analyzed.

    Results: For similar age, body mass index, and fat mass index, MHO women (n = 40) showed higher insulin sensitivity levels and a more favorable cardiometabolic profile than MAO women (n = 36), as evidenced by a 2-fold increase in glucose disposal rates measured by the hyperinsulinemic-euglycemic clamp (P = .001). Among 18 detectable pollutants measured, MAO women had higher plasma concentrations of 12 POPs (fold increase, 1.4-2.9; P < .001-.036). Logistic regression analyses showed that the prevalence of the MAO phenotype was significantly associated with higher levels of total dioxin and non-dioxin-like polychlorinated biphenyls (odds ratio, 4.7; 95% confidence interval, 1.8-12.5; P = .002), as well as trans-nonachlor (odds ratio, 6.1; 95% CI, 2.2-16.4; P < .001).

    Conclusion: Our study demonstrates that the metabolically healthy and abnormal phenotypes have distinct plasma POP profiles.

  • 11. 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.

  • 12.
    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.

  • 13. Hultin, Hella
    et al.
    Hellman, Per
    Lundgren, Ewa
    Olovsson, Matts
    Ekbom, Anders
    Rastad, Jonas
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Association of parathyroid adenoma and pregnancy with preeclampsia2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 9, p. 3394-3399Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Case reports have described associations between calcium metabolism disturbances and primary hyperparathyroidism with preeclampsia, suggesting parathyroid involvement in preeclampsia etiology. This study examines whether parathyroid adenoma, the main cause of hyperparathyroidism, diagnosed and treated before pregnancy is associated with preeclampsia. DESIGN: We conducted a register-based study to assess the association between parathyroid adenoma and subsequent preeclampsia. SETTING: Births among Sweden's general population were studied. POPULATION: The study population included 52 women with a diagnosis of parathyroid adenoma and 519 without, all of whom had a subsequent singleton pregnancy between 1973 and 1997. METHODS: We performed a conditional logistic regression investigating the association of parathyroid adenoma with subsequent preeclampsia in the first singleton pregnancy with adjustment for potential confounding factors. MAIN OUTCOME MEASURE: The main outcome was a diagnosis of preeclampsia that does not include women with prior chronic hypertension. To ensure that treatment of parathyroid adenoma was completed before pregnancy, those with a diagnosis of parathyroid adenoma made less than 2 yr before delivery (and the matched comparison women) were excluded. RESULTS: Statistically, parathyroid adenoma prior to delivery is significantly (P < 0.001) associated with preeclampsia, producing an adjusted odds ratio of 6.89 (95% confidence interval, 2.30, 20.58). CONCLUSION: A history of parathyroid adenoma should be viewed as a risk for preeclampsia.

  • 14.
    Lebwohl, Benjamin
    et al.
    Celiac Disease Center, Department of Medicine, Columbia University College of Physicians, New York NY, United States; Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Michaelsson, Karl
    Department of Surgical Sciences, Section of Orthopaedics, Uppsala University, Uppsala, Sweden.
    Green, Peter H. R.
    Celiac Disease Center, Department of Medicine, Columbia University College of Physicians, New York NY, United States.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Persistent Mucosal Damage and Risk of Fracture in Celiac Disease2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 2, p. 609-616Article in journal (Refereed)
    Abstract [en]

    Context: Celiac disease (CD) is associated with an increased fracture risk, an increase that persists after diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy.

    Objective: The objective of the study was to determine whether persistent VA impacts long-term fracture risk.

    Design: This was a cohort study.

    Setting and Patients: We identified all patients in Sweden with histological evidence of CD who underwent a follow-up biopsy and compared patients with persistent VA with those with mucosal healing.

    Main Outcome Measures: The following were measured: 1) any fracture; 2) likely osteoporotic fracture (defined as fractures of the hip, distal forearm, thoracic and lumbar spine, or proximal humerus); and 3) hip fracture.

    Results: Of 7146 patients, VA was present on follow-up biopsy in 43%. There was no significant association between persistent VA and overall fractures [hazard ratio (HR) of persistent VA compared with those with healing 0.93, 95% confidence interval (CI) 0.82-1.06] or with likely osteoporotic fractures (HR 1.11, 95% CI 0.84-1.46). Persistent VA was associated with an increased risk of hip fracture (HR 1.67, 95% CI 1.05-2.66). Hip fracture risk increased, depending on the degree of VA (HR for partial VA compared with those with healing 1.70, 95% CI 0.82-3.49, HR for subtotal/total VA compared with those with healing 2.16, 95% CI 1.06-4.41).

    Conclusions: Persistent VA on follow-up biopsy is predictive of hip fracture risk. The association between persistent VA and hip fractures, but not fractures overall, implies that thinner sc tissue

  • 15.
    Ljungqvist, Olle
    Örebro University, School of Health and Medical Sciences.
    Insulin resistance and outcomes in surgery2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 9, p. 4217-4219Article in journal (Refereed)
  • 16.
    Ludvigsson, Jonas F.
    et al.
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Kampe, Olle
    Department of Medical Sciences, University Hospital, Uppsala University, Uppsala, Sweden.
    Lebwohl, Benjamin
    Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Green, Peter H. R.
    Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Silverberg, Shonni J.
    Division of Endocrinology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Ekbom, Anders
    Department of Medical Sciences, University Hospital, Uppsala University, Uppsala, Sweden.
    Primary Hyperparathyroidism and Celiac Disease: A Population-Based Cohort Study2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 3, p. 897-904Article in journal (Refereed)
    Abstract [en]

    Context: Celiac disease (CD) has been linked to several endocrine disorders, including type 1 diabetes and thyroid disorders, but little is known regarding its association to primary hyperparathyroidism (PHPT).

    Objective: The aim of the study was to examine the risk of PHPT in patients with CD.

    Design and Setting: We conducted a two-group exposure-matched nonconcurrent cohort study in Sweden. A Cox regression model estimated hazard ratios (HR) for PHPT.

    Participants: We identified 17,121 adult patients with CD who were diagnosed through biopsy reports (Marsh 3, villous atrophy) from all 28 pathology departments in Sweden. Biopsies were performed in 1969-2008, and biopsy report data were collected in 2006-2008. Statistics Sweden then identified 85,166 reference individuals matched with the CD patients for age, sex, calendar period, and county.

    Main Outcome Measure: PHPT was measured according to the Swedish national registers on inpatient care, outpatient care, day surgery, and cancer.

    Results: During follow-up, 68 patients with CD and 172 reference individuals developed PHPT(HR = 1.91; 95% confidence interval = 1.44-2.52). The absolute risk of PHPT was 42/100,000 person-years with an excess risk of 20/100,000 person-years. The risk increase for PHPT only occurred in the first 5 yr of follow-up; after that, HR were close to 1 (HR = 1.07; 95% confidence interval = 0.70-1.66).

    Conclusions: CD patients are at increased risk of PHPT, but the absolute risk is small, and the excess risk disappeared after more than 5 yr of follow-up. (J Clin Endocrinol Metab 97: 897-904, 2012)

  • 17.
    Lui, Julian C.
    et al.
    National Institutes of Health, .
    Barnes, Kevin M.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Dong, Lijin
    Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda MD, USA.
    Yue, Shanna
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Graber, Evan
    Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA.
    Rapaport, Robert
    Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA.
    Dauber, Andrew
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA; Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Örebro University Hosptial, Örebro, Sweden.
    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.
    Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity2018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 4, p. 1470-1478Article in journal (Refereed)
    Abstract [en]

    Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in EZH2, a histone methyltransferase responsible for H3K27 trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.

    Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome either cause a gain of function or a partial loss of function.

    Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.

    Results: A de novo missense EZH2 mutation (c.1876G>A (p.Val626Met)) was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality while heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.

    Conclusion: We generated a mouse model with the same mutation as our patient and found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

  • 18. Rask, Eva
    et al.
    Olsson, T.
    Soderberg, S.
    Andrew, R.
    Livingstone, D. E.
    Johnson, O.
    Walker, B. R.
    Tissue-specific dysregulation of cortisol metabolism in human obesity2001In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 86, no 3, p. 1418-1421Article in journal (Refereed)
    Abstract [en]

    Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local pre-receptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1). In obese Zucker rats 11 beta -HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin sensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from le participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r=0.47, p<0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r=0.43, p<0.02), and converted less cortisone to cortisol after oral administration (r=-0.49, p<0.01), suggesting impaired hepatic 11<beta>-HSD1 activity. By contrast, in vitro 11 beta -HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r=0.66, p<0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11<beta>-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11 beta -HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.

  • 19.
    Rask, Eva
    et al.
    Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden .
    Walker, Brian R.
    Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Söderberg, Stefan
    Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden .
    Livingstone, Dawn E. W.
    Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Eliasson, Mats
    Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden .
    Johnson, Owe
    Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden .
    Andrew, Ruth
    Department of Medical Sciences, University of Edinburgh, Edinburgh, Western General Hospital, UK.
    Olsson, Tommy
    Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden .
    Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity2002In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 87, no 7, p. 3330-6Article in journal (Refereed)
    Abstract [en]

    Cushing's syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11beta-HSD1 activity in women with moderate obesity and insulin resistance. Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11beta-HSD type 1 activity in vitro. Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5alpha- and, to a lesser extent, 5beta-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11beta-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 +/- 28,528, 115,903 +/- 26,032, and 90,460 +/- 18,590 nmol/liter.min; P < 0.001). However, 11beta-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05). In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.

  • 20.
    Simonyte, Kotryna
    et al.
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Olsson, Tommy
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Näslund, Ingmar
    Departments of Surgery, Örebro University Hospital, Örebro, Sweden.
    Angelhed, Jan-Erik
    Department of Medicine, Sahlgrenska Academy, Gothenburg, Sweden;.
    Lönn, Lars
    Department of Radiology and Vascular Surgery, Faculty of Health Sciences, Rigshospitalet, Copenhagen, Denmark.
    Mattsson, Cecilia
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Rask, Eva
    Örebro University Hospital, Örebro, Sweden.
    Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 7, p. 3527-31Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: The role of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in the pathogenesis of obesity has been elucidated in humans and in various rodent models. Obesity is accompanied by disturbances in glucocorticoid metabolism, circulating adipokine levels, and fatty acid (FA) reesterification. This study was undertaken to evaluate glucocorticoid metabolism in sc fat before and after weight loss and to explore putative associations between 11beta-HSD1 and leptin, adiponectin, and FA recycling.

    SUBJECTS AND METHODS: Twenty-seven obese (mean body mass index 44.4 + or - 4.4 kg/m(2)) women underwent gastric bypass surgery. Subcutaneous fat biopsies were collected before and 2 yr after surgery. The expression of 11beta-HSD1, leptin, adiponectin, and phosphoenolpyruvate carboxykinase (PEPCK) mRNA was evaluated with real-time PCR. Serum leptin and adiponectin protein levels were estimated by ELISA.

    RESULTS: Two years after gastric bypass surgery, significant reductions were observed in the mean body mass index (from 44.4 to 30.8 kg/m(2)) and mean waist circumference (from 121.9 to 90.6 cm). After weight loss, 11beta-HSD1 mRNA expression decreased 4-fold (P < 0.001). Both leptin and adiponectin mRNA expression decreased, with concomitantly decreased circulating leptin and increased circulating adiponectin levels. PEPCK mRNA expression did not change.

    CONCLUSION: Weight loss after gastric bypass surgery was followed by metabolically favorable changes in insulin sensitivity, circulating leptin and adiponectin, and peripheral glucocorticoid metabolism. A significant reduction in 11beta-HSD1 expression was observed in sc adipose tissue after weight loss. This suggests that up-regulation of 11beta-HSD1 is a consequence, rather than a cause, of obesity.

  • 21.
    Thorell, Anders
    et al.
    Karolinska Institutet, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm.
    Rooyackers, Olav
    Department of Anaesthesiology and Intensive Care, Huddinge University Hospital, Stockholm.
    Myrenfors, Peter
    Karolinska Institutet, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm.
    Soop, Mattias
    Karolinska Institutet, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm.
    Nygren, Jonas
    Karolinska Institutet, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm.
    Ljungqvist, Olle
    Karolinska Institutet, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm.
    Intensive insulin treatment in critically ill trauma patients normalizes glucose by reducing endogenous glucose production2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 11, p. 5382-6Article in journal (Refereed)
    Abstract [en]

    Critical illness is associated with insulin resistance and hyperglycemia. Intensive insulin treatment to normalize blood glucose during feeding has been shown to improve morbidity and mortality in patients in intensive care. The mechanisms behind the glucose-controlling effects of insulin in stress are not well understood. Six previously healthy, severely traumatized patients (injury severity score > 15) were studied early (24-48 h) after trauma. Endogenous glucose production (EGP) and whole-body glucose disposal (WGD) were measured (6,6-(2)H(2)-glucose) at basal, during total parenteral nutrition (TPN), and during TPN plus insulin to normalize blood glucose (TPN+I). Six matched volunteers served as controls. At basal and TPN, concentrations of glucose and insulin were higher in patients (P < 0.05). During TPN+I, insulin concentrations were 30-fold higher in patients. At basal, WGD and EGP were 30% higher in patients (P < 0.05). During TPN, EGP decreased in both groups but less in patients, resulting in 110% higher EGP than controls (P < 0.05). Normoglycemia coincided with reduced EGP, resulting in similar rates in both groups. WGD did not change during TPN or TPN+I and was not different between the groups. In conclusion, in healthy subjects, euglycemia is maintained during TPN at physiological insulin concentrations by a reduction of EGP, whereas WGD is maintained at basal levels. In traumatized patients, hyperglycemia is due to increased EGP. In contrast to controls, normalization of glucose concentration during TPN needs high insulin infusion rates and is accounted for by a reduction in EGP, whereas WGD is not increased.

  • 22. van Vught, Anneke J. A. H.
    et al.
    Nieuwenhuizen, Arie G.
    Brummer, Robert
    Örebro University, School of Health and Medical Sciences.
    Westerterp-Plantenga, Margriet S.
    Effects of oral ingestion of amino acids and proteins on the somatotropic axis2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 2, p. 584-590Article in journal (Refereed)
    Abstract [en]

    CONTEXT: GH is an important regulator of growth and body composition. It has been shown that GH release can be promoted by iv as well as oral administration of various amino acids (AAs), especially arginine (ARG) and lysine (LYS), which are amply present in soy protein. However, the effects of dietary protein on GH secretion are less well described. OBJECTIVE AND DESIGN: In an experiment, we compared the effects of oral ingestion of a mixture reflecting the AA composition of soy protein (AA), with oral ingestion of ARG + LYS, on GH secretion in eight healthy women (body mass index 19-25 kg/m(2); age, 18-24 yr). In a second experiment, we compared oral ingestion of hydrolyzed soy protein and complete soy protein with the AA mixture on GH secretion in eight healthy women (body mass index 19-26 kg/m(2); age, 19-36 yr). Both experiments were performed in a randomized, single-blind crossover design. GH, insulin, glucose, and plasma AA were determined every 20 min, during 3 h in the first experiment and during 5 h in the second experiment. RESULTS: Peak values of GH were higher after ingestion of the AA mixture compared with ingestion of ARG + LYS (P < 0.05). GH responses, as determined by area under the curve, did not significantly differ after ingestion of the complete soy protein, hydrolyzed soy protein, or AA mixture but were all higher than after placebo (P < 0.05). Insulin responses (area under the curve) were higher after ingestion of hydrolyzed soy protein, complete soy protein, and AA mixture, compared with placebo (P < 0.05). Glucose concentrations were unaffected. CONCLUSION: Ingestion of soy protein, either hydrolyzed or intact, as well as AAs reflecting soy protein, stimulates GH release to a similar extent.

  • 23. Wake, Deborah J.
    et al.
    Rask, Eva
    Livingstone, Dawn E. W.
    Söderberg, Stefan
    Olsson, Tommy
    Walker, Brian R.
    Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.2003In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, no 8, p. 3983-8Article in journal (Refereed)
    Abstract [en]

    In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

  • 24. Witasp, Anna
    et al.
    Nordfors, Louise
    Schalling, Martin
    Nygren, Jonas
    Ljungqvist, Olle
    Örebro University, School of Health and Medical Sciences.
    Thorell, Anders
    Expression of inflammatory and insulin signaling genes in adipose tissue in response to elective surgery2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 7, p. 3460-3469Article in journal (Refereed)
    Abstract [en]

    Context: The mechanisms behind postoperative insulin resistance and impaired glucose utilization are not fully understood. Objective: In this study, we aimed to specifically evaluate the transcription profile of genes in the insulin and adipokine signaling pathways in sc and omental adipose tissue after surgical injury. Design: Relative expression of 21 target genes was analyzed in both sc and omental adipose tissue sampled at the beginning and at the end of operation. Setting: The study was conducted at a university-affiliated hospital. Patients: Twelve nondiabetic patients [seven females; age, 65 (range, 46-72) yr; body mass index, 24.8 (16.5-29.8) kg/m(2)] undergoing major abdominal surgery were included. Main Outcome Measurements: The changes in mRNA levels were analyzed. Results: After surgery, both sc and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced (P < 0.05). TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue. Conclusions: The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery, and this pattern differs between different fat depots. This could be of importance for the metabolic aberrations associated to postsurgical complications, such as insulin resistance and hyperglycemia. (J Clin Endocrinol Metab 95: 3460-3469, 2010)

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