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  • 251.
    Georgakis, Marios K.
    et al.
    Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias Str, Athens 11527, Greece..
    Kalogirou, Eleni I.
    Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias Str, Athens 11527, Greece..
    Diamantaras, Andreas-Antonios
    Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias Str, Athens 11527, Greece.;Charite, Program Med Neurosci, D-10117 Berlin, Germany..
    Daskalopoulou, Stella S.
    McGill Univ, Fac Med, Dept Med, Div Internal Med, Montreal, PQ H3G 1A4, Canada..
    Munro, Cynthia A.
    Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA..
    Lyketsos, Constantine G.
    Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA..
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Petridou, Eleni Th.
    Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias Str, Athens 11527, Greece..
    Age at menopause and duration of reproductive period in association with dementia and cognitive function: A systematic review and meta-analysis2016In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 73, p. 224-243Article, review/survey (Refereed)
    Abstract [en]

    Introduction: The preponderance of dementia among postmenopausal women compared with same-age men and the female sex hormones neuroprotective properties support a tentative role of their deficiency in the dementia pathogenesis. Methods: Pairs of independent reviewers screened 12,323 publications derived from a search strategy for MEDLINE to identify articles investigating the association of age at menopause/reproductive period with (i) dementia and (ii) cognitive function; a snowball of eligible articles and reviews was conducted and authors were contacted for additional information. Random-effect models were used for the meta analysis. Results: Age at menopause (13 studies; 19,449 participants) and reproductive period (4 studies; 9916 participants) in the highest categories were not associated with odds of dementia (effect size [ES]: 0.97 [0.78-1.21]) and Alzheimer's disease (ES: 1.06 [0.71-1.58]). Significant heterogeneity was however noted in both analyses (12: 63.3%, p = 0.003 and 12: 72.6%, p = 0.01, respectively). Subgroup analyses by outcome assessment, study design, level of adjustment and study quality did not materially change the findings. In 9/13 studies assessing cognitive function, advanced age at menopause/longer reproductive period was significantly associated with better cognitive performance/lower decline. Due to statistical differences, no meta-analysis was possible for cognitive function. Conclusions: Existing evidence does not support an association between indices of prolonged exposure to female hormones and lower dementia risk. There are indications, however, for better cognitive performance and delayed cognitive decline, supporting a link between female hormone deficiency and cognitive aging. Current literature limitations, indicated by the heterogeneous study-set, point towards research priorities in this clinically relevant area.

  • 252.
    Ghadzi, Siti Maisharah Sheikh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacometrics Modelling in Type 2 Diabetes Mellitus: Implications on Study Design and Diabetes Disease Progression2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pharmacometric modelling is widely used in many aspects related to type 2 diabetes mellitus (T2DM), for instance in the anti-diabetes drug development, and in quantifying the disease progression of T2DM.

    The aim of this thesis were to improve the design of early phase anti-diabetes drug development studies with the focus on the power to identify mechanism of drug action (MoA), and to characterize and quantify the progression from prediabetes to overt diabetes, both the natural progression and the progression with diet and exercise interventions, using pharmacometrics modelling.

    The appropriateness of a study design depends on the MoAs of the anti-hyperglycaemic drug. Depending on if the focus is power to identify drug effect or accuracy and precision of drug effect, the best design will be different. Using insulin measurements on top of glucose has increase the power to identify a correct drug effect, distinguish a correct MoA from the incorrect, and to identify a secondary MoA in most cases. The accuracy and precision of drug parameter estimates, however, was not affected by insulin. A natural diabetes disease progression model was successfully added in a previously developed model to describe parameter changes of glucose and insulin regulation among impaired glucose tolerance (IGT) subjects, with the quantification of the lifestyle intervention. In this model, the assessment of multiple short-term provocations was combined to predict the long-term disease progression, and offers apart from the assessment of the onset of T2DM also the framework for how to perform similar analysis. Another previously published model was further developed to characterize the weight change in driving the changes in glucose homeostasis in subjects with IGT. This model includes the complex relationship between dropout from study and weight and glucose changes.

    This thesis has provided a first written guidance in designing a study for pharmacometrics analysis when characterizing drug effects, for early phase anti-diabetes drug development. The characterisation of the progression from prediabetes to overt diabetes using pharmacometrics modelling was successfully performed. Both the natural progression and the progression with diet and exercise interventions were quantified in this thesis.

    List of papers
    1. The impact of insulin measurements in oral glucose tolerance test: a simulation study in type 2 diabetes to assess power to characterize drug effects
    Open this publication in new window or tab >>The impact of insulin measurements in oral glucose tolerance test: a simulation study in type 2 diabetes to assess power to characterize drug effects
    (English)Article in journal (Other academic) Submitted
    Keywords
    study power, insulin measurements, oral glucose tolerance test, drug effects
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-316810 (URN)
    Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2018-01-13
    2. Study Design Selection in Early Clinical Anti-Hyperglycemic Drug Development: A Simulation Study of Glucose Tolerance Tests
    Open this publication in new window or tab >>Study Design Selection in Early Clinical Anti-Hyperglycemic Drug Development: A Simulation Study of Glucose Tolerance Tests
    2018 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 7, no 7, p. 432-441Article in journal (Refereed) Published
    Abstract [en]

    In antidiabetic drug development, phase I studies usually involve short-term glucose provocations. Multiple designs are available for these provocations (e.g., meal tolerance tests (MTTs) and graded glucose infusions (GGIs)). With a highly nonlinear, complex system as the glucose homeostasis, the various provocations will contribute with different information offering a rich choice. Here, we investigate the most appropriate study design in phase I for several hypothetical mechanisms of action of a study drug. Five drug effects in diabetes therapeutic areas were investigated using six study designs. Power to detect drug effect was assessed using the likelihood ratio test, whereas precision and accuracy of the quantification of drug effect was assessed using stochastic simulation and estimations. An overall summary was developed to aid designing the studies of antihyperglycemic drug development using model-based analysis. This guidance is to be used when the integrated glucose insulin model is used, involving the investigated drug mechanisms of action.

    Keywords
    Phase I clinical trials, study design, power, precision, pharmacometric simulations
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-316819 (URN)10.1002/psp4.12302 (DOI)000439996200002 ()29732710 (PubMedID)
    Note

    Correction in: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, Volume: 8, Issue: 7, Pages: 520-520, DOI: 10.1002/psp4.12391

    Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2019-08-19Bibliographically approved
    3. Mathematical diabetes disease progression modeling in the integrated glucose-insulin (IGI) model among impaired glucose tolerance subjects from the Finnish Diabetes Prevention Study
    Open this publication in new window or tab >>Mathematical diabetes disease progression modeling in the integrated glucose-insulin (IGI) model among impaired glucose tolerance subjects from the Finnish Diabetes Prevention Study
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    mathematical model, impaired glucose tolerance, diabetes disease progression model, lifestyle intervention, insulin secretion, insulin sensitivity
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-316825 (URN)
    Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2018-01-13
    4. Model-based quantification of the natural diabetes disease progression and lifestyle intervention effects on weight, beta cell function and insulin sensitivity for subjects with impaired glucose tolerance
    Open this publication in new window or tab >>Model-based quantification of the natural diabetes disease progression and lifestyle intervention effects on weight, beta cell function and insulin sensitivity for subjects with impaired glucose tolerance
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Model-based, impaired glucose tolerance, diabetes disease progression model, lifestyle intervention, insulin sensitivity, beta cell function, postprandial glucose, weight, fasting plasma glucose, fasting serum insulin, HbA1c
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-316834 (URN)
    Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2018-01-13
  • 253.
    Ghadzi, Siti Maisharah Sheikh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Mello, V. D.
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Joensuu, Finland..
    Uusitupa, M.
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Joensuu, Finland..
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A mathematical disease progression model for the effect of diet and exercise in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study (FDPS)2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S192-S192Article in journal (Other academic)
  • 254.
    Ghandour, Rula
    et al.
    Birzeit Univ, ICPH, Birzeit, Palestine.
    Mikki, Nahed
    Birzeit Univ, ICPH, Birzeit, Palestine.
    Abu Rmeileh, Niveen M. E.
    Birzeit Univ, ICPH, Birzeit, Palestine.
    Jerden, Lars
    Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Norberg, Margareta
    Umea Univ, Dept Publ Hlth & Clin Med, Unit Epidemiol & Global Hlth, Umea, Sweden.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Husseini, Abdullatif
    Birzeit Univ, ICPH, Birzeit, Palestine.
    Complications of type 2 diabetes mellitus in Ramallah and al-Bireh: The Palestinian Diabetes Complications and Control Study (PDCCS)2018In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 12, no 6, p. 547-557Article in journal (Refereed)
    Abstract [en]

    Background: Type 2 diabetes mellitus (T2DM) is a growing pandemic that will lead, if not managed and controlled, to frequent complications, poor quality of life, and high rates of disability and death. Little is known about T2DM complications in Palestine. The aim of this study is to estimate the prevalence of T2DM complications in Ramallah and al-Bireh governorate of Palestine. Methods: The study was conducted in eleven primary healthcare clinics offering services for persons with T2DM. Macrovascular complications were assessed using the Diabetes complication index. Microvascular complications were measured by physical examinations and laboratory tests. Questionnaires, laboratory tests, and physical examinations were used to assess socio-demographic characteristics, co-morbidities and other risk factors. Results: 517 adult men and nonpregnant women participated in the study (166 men, 351 women). The response rate was 84%. Mean age and mean duration of diabetes were 58.1 and 9.4 years respectively. Prevalence of diagnosed microvascular and macrovascular complications was 67.2% and 28.6% respectively. 78.2% of the participants had poor glycemic control (HbA1c >= 7.0%). Conclusion: Significant proportions of persons with T2DM had macro- and microvascular complications and poor metabolic control. These findings are important for policy development and the planning of health services.

  • 255.
    Ghanni, Simat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kartläggning av förskrivningen av inkretinbaserade diabetesläkemedel från primärvården inom Uppsala läns landsting2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Studier har visat att intensiv blodglukossänkande behandling vid typ 2-diabetes mellitus (T2DM) har en liten eller ingen effekt på mikro- resp. makrovaskulära komplikationer för patienter med diabetesduration på 8-12 år. Enligt Socialstyrelsens nationella riktlinjer för diabetesvård har glucagon like peptide -1 (GLP-1)-analoger och dipeptidyl peptidase-4 (DPP-4)-hämmare låg prioritet vid behandling av T2DM. Data på effekt och säkerhet för långtidsbehandling med dessa läkemedel är begränsad.

    Syfte: Att kartlägga förskrivningen av inkretinbaserade läkemedel hos patienter med T2DM från primärvården inom Uppsala läns landsting under perioden 2008-2012.

    Material och metoder: En tvärsnittstudie baserad på patientjournaler. Materialet bestod av 149 patienter resp. 779 patienter som förskrivits en GLP-1-analog resp. en DPP-4-hämmare. Genom journalgranskning i Cosmic insamlades information om bl.a. ålder, HbA1c och diabetesduration. Det kontrollerades också om behandlingen följdes upp under första året efter insättningen.

    Resultat: 129 patienter resp. 171 patienter som förskrivits en GLP-1-analog resp. en DPP-4-hämmare inkluderades i studien. Genomsnittlig ålder i studiepopulationen för resp. läkemedelsgrupp var 55,3 år och 62,3 år, diabetesdurationen var 8,4 år resp. 9,3 år och HbA1c-medelvärdet var 76,5 mmol/mol resp. 71,3 mmol/mol. Behandlingen följdes upp under första insättningsåret hos ca 90 % av patienterna i resp. läkemedelsgrupp.

    Konklusion: Drygt hälften av studiepopulationen hade ett HbA1c på över 70 mmol/mol vid insättning av inkretinläkemedel, vilket sannolikt är en adekvat insättningsorsak för dessa läkemedel. Däremot hade en femtedel ett HbA1c under 60 mmol/mol. Man kan väcka frågan om vilka effekter och bieffekter ytterligare blodglukossänkande behandling har för dessa patienter.

  • 256.
    Giandomenico, Valeria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cui, Tao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pelosi, Giuseppe
    European Institute of Oncology, Milan, Italy; University of Milan School of Medicine, Milan, Italy.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Olfactory Receptor 51E1 as a Novel Target for Diagnosis in Somatostatin Receptor Negative Lung Carcinoids2013In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 51, p. 277-286Article in journal (Refereed)
    Abstract [en]

    Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors.

  • 257.
    Giandomenico, Valeria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Thirlwell, Chrissie
    UCL Canc Inst, Med Genom Lab, Canc Res UK, London, England..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Other Novel Therapies: Biomarkers, microRNAs and microRNA Inhibitors, DNA Methylation, Epigenetics, Immunotherapy and Virotherapy2015In: Neuroendocrine Tumors: A Multidisciplinary Approach / [ed] Papotti, M; DeHerder, WW, S. Karger, 2015, p. 248-262Chapter in book (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) consist of heterogeneous neoplasms. The neuroendocrine cells of the human body are confined to certain organs, such as the thyroid, pancreas and adrenals, or they are dispersed throughout the body in the respiratory tract and in the intestinal mucosa. The cells belong to the diffuse endocrine cell system, share a neuroendocrine phenotype, and accumulate precursor molecules which are then processed into hormones, peptides or amines. The tightly controlled release on stimulation is either to the blood stream or adjacent cells or neurons. Neuroendocrine cells regulate various processes in the human body, such as gastrointestinal secretion, blood pressure and response to stress. NETs present a wide spectrum of malignant diseases from rather benign to very malignant and lethal variants. NETs may occur in any organ, but are mainly detected in the gastroenteropancreatic system and in the lungs. The understanding of NET biology and treatments has changed dramatically during the last decade. Today, the main problems that clinicians and translational scientists face in overcoming these malignancies relate to various aspects within the molecular pathogenesis of NETs. This chapter focuses on the importance of novel biomarkers: microRNA and microRNA inhibitors; DNA methylation and epigenetics, and immunotherapy and virotherapy to develop novel treatments for NETs.

  • 258.
    Gillberg, Linn
    et al.
    Rigshosp, Dept Endocrinol, Sect 7652,Tagensvej 20, DK-2200 Copenhagen N, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Perfilyev, Alexander
    Lund Univ, Dept Clin Sci, Epigenet & Diabet Unit, Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden..
    Brons, Charlotte
    Rigshosp, Dept Endocrinol, Sect 7652,Tagensvej 20, DK-2200 Copenhagen N, Denmark..
    Thomasen, Martin
    Rigshosp, Dept Endocrinol, Sect 7652,Tagensvej 20, DK-2200 Copenhagen N, Denmark..
    Grunnet, Louise G.
    Rigshosp, Dept Endocrinol, Sect 7652,Tagensvej 20, DK-2200 Copenhagen N, Denmark..
    Volkov, Petr
    Lund Univ, Dept Clin Sci, Epigenet & Diabet Unit, Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden..
    Rosqvist, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Iggman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Dahlman, Ingrid
    Huddinge Univ Hosp, Karolinska Inst, Dept Med, S-14186 Huddinge, Sweden..
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Rönn, Tina
    Lund Univ, Dept Clin Sci, Epigenet & Diabet Unit, Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden..
    Nilsson, Emma
    Rigshosp, Dept Endocrinol, Sect 7652,Tagensvej 20, DK-2200 Copenhagen N, Denmark.;Lund Univ, Dept Clin Sci, Epigenet & Diabet Unit, Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden..
    Vaag, Allan
    Rigshosp, Dept Endocrinol, Sect 7652,Tagensvej 20, DK-2200 Copenhagen N, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Ling, Charlotte
    Lund Univ, Dept Clin Sci, Epigenet & Diabet Unit, Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden..
    Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 4, p. 799-812Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. Methods mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. Results We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate < 5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate < 5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Conclusions/interpretation Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

  • 259.
    Gkourogianni, Alexandra
    et al.
    Karolinska Inst & Karolinska Univ Hosp, Div Pediat Endocrinol, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden.
    Andrew, Melissa
    Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 70941 USA.
    Tyzinski, Leah
    Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 70941 USA.
    Crocker, Melissa
    Boston Childrens Hosp, Endocrinol, Boston, MA USA.
    Douglas, Jessica
    Boston Childrens Hosp, Boston, MA 02115 USA.
    Dunbar, Nancy
    Div Pediat Endocrinol, Connecticut Childrens Med Ctr, Hartford, CT 06106 USA.
    Fairchild, Jan
    Charles Univ Prague & Univ Hosp Motol, Second Fac Med, Dept Pediat, Prague 11636, Czech Republic. Phoenix Childrens Hosp, Divis Endocrinol, Phoenix, AZ 85016 USA;Womens & Childrens Hosp, Dept Endocrinol & Diabet, South Australia 5006, Australia.
    Funari, Mariana F. A.
    Univ S ao Paulo, Unidade Endocrinologia Desenvolvimento LIM 42, Disciplina Endocrinologia, Faculdade Medicina, BR-05508020 Sao Paulo, Brazil.
    Heath, Karen E.
    Univ Auto noma Madrid, Hosp Univ Paz, Inst Med & Mol Genet INGEMM & Skeletal Dysplasia, IdiPAZ, Madrid 20849, Spain.
    Jorge, Alexander A. L.
    Univ S ao Paulo, Unidade Endocrinologia Desenvolvimento LIM 42, Disciplina Endocrinologia, Faculdade Medicina, BR-05508020 Sao Paulo, Brazil.
    Kurtzman, Tracey
    El Rio Community Hlth Ctr, Tucson, AZ 85745 USA.
    LaFranchi, Stephen
    Charles Univ Prague & Univ Hosp Motol, Second Fac Med, Dept Pediat, Prague 11636, Czech Republic. Phoenix Childrens Hosp, Divis Endocrinol, Phoenix, AZ 85016 USA.
    Lalani, Seema
    Molecular & Human Genet, Dublin, Ireland.
    Lebl, Jan
    Lin, Yuezhen
    Baylor Coll Med, Pediatr Endocrinol & Metab, Houston, TX 77030 USA.
    Los, Evan
    Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA.
    Newbern, Dorothee
    Nowak, Catherine
    Boston Childrens Hosp, Boston, MA 02115 USA.
    Olson, Micah
    Popovic, Jadranka
    Univ Pittsburgh Med Ctr, Childrens Hosp Pittsburgh, Pittsburgh, PA 15237 USA.
    pruhova, Stepanka
    Elblova, Lenka
    Charles Univ Prague & Univ Hosp Motol, Second Fac Med, Dept Pediat, Prague 11636, Czech Republic. Phoenix Childrens Hosp, Divis Endocrinol, Phoenix, AZ 85016 USA.
    Quintos, Jose Bernardo
    Childrens Hosp, Providence, RI 02903 USA.
    Segerlund, Emma
    Karolinska Inst & Karolinska Univ Hosp, Div Pediat Endocrinol, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden;Sunderby Hosp, S-95442 Sunderby, Sweden.
    Sentchordi, Lucia
    Hosp Univ Infanta Sofia, Dept Pediat, Madrid 28703, Spain;Univ Auto noma Madrid, Hosp Univ Paz, Inst Med & Mol Genet INGEMM & Skeletal Dysplasia, IdiPAZ, Madrid 20849, Spain.
    Shinawi, Marwan
    Washington Univ, Divis Genet, St Louis, MO 63130 USA.
    Stattin, Evalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Swartz, Jonathan
    Boston Childrens Hosp, Endocrinol, Boston, MA USA.
    Gonzalez del Angel, Ariadna
    Inst Nacl Pediat, Dept Gene tica Humana, Lab Biolog Mol Insurgentes Cuicuilco, Insurgentes Cuicuilco, Mexico City 04530, DF, Mexico.
    Cuellar, Sinhue Diaz
    Inst Nacl Pediat, Dept Gene tica Humana, Lab Biolog Mol Insurgentes Cuicuilco, Insurgentes Cuicuilco, Mexico City 04530, DF, Mexico.
    Hosono, Hidekazu
    Childrens Med Ctr, Santa Barbara, CA 93111 USA.
    Sanchez-Lara, Pedro A.
    Childrens Hosp Angeles, Ctr Personalized Med, Los Angeles, CA 90027 USA.
    Hwa, Vivian
    Baron, Jeffrey
    Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Sect Growth & Dev, Bethesda, MD 20892 USA.
    Nilsson, Ola
    Karolinska Inst & Karolinska Univ Hosp, Div Pediat Endocrinol, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden;Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Sect Growth & Dev, Bethesda, MD 20892 USA.
    Dauber, Andrew
    Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 70941 USA;Orebro Univ & Univ Hosp, Department ofMed Sci, S-70185 Orebro, Sweden.
    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 accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 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 the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, + 1.3 years; range, + 0.0 to + 3.7 years). Nineteen individuals had received growth hormone therapy 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. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

  • 260. Glasberg, S.
    et al.
    Thomas, D.
    Strosberg, J. R.
    Pape, U. F.
    Felder, S.
    Tsolakis, Apostolos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Alexandraki, K.
    Fraenkel, M.
    Saiegh, L.
    Reissman, P.
    Kaltsas, G.
    Gross, D. J.
    Metastatic Type 1 Gastric Carcinoid-A Real Threat or Just a Myth?2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 302-302Article in journal (Other academic)
  • 261. Goldberg, Rachel
    et al.
    Rubinstein, Ariel M.
    Gil, Natali
    Hermano, Esther
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van der Vlag, Johan
    Atzmon, Ruth
    Meirovitz, Amichay
    Elkin, Michael
    Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4302-4313Article in journal (Refereed)
    Abstract [en]

    Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, diabetic nephropathy (DN) became the leading cause of end-stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in individuals with DN. These events are fueled by heterotypic interactions among glomerular, tubular, and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and posttranslationally activated by cathepsin L of tubular origin, sustains continuous activation of kidney-damaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury. Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.

  • 262. Gonzalez, V
    et al.
    Lindblad, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Renlund, M
    Rangsten, P
    Huss, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    A first clinical verification of a radio frequency-based spectroscopy sensor intended for glucose detection in interstitial fluid.2017In: Diabetes Technology & Therapeutics, ISSN 1520-9156, E-ISSN 1557-8593, Vol. 19, no S1Article in journal (Refereed)
  • 263.
    Goroshchuk, Oksana
    et al.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Attarha, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Andersson, Sonia
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Mints, Miriam
    Karolinska Inst, S-10401 Stockholm, Sweden..
    PKN1 overexpression as a predictor of poor survival in endometrial cancer2016In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 32, p. 117-117Article in journal (Other academic)
  • 264.
    Gotthardt, Martin
    et al.
    Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, POB 9101, NL-6500 HB Nijmegen, Netherlands.
    Eizirik, Decio L.
    Univ Libre Bruxelles, Fac Med, ULB Ctr Diabet Res, Brussels, Belgium.
    Aanstoot, Henk-Jan
    Ctr Pediat & Adolescent Diabet Care & Res, Diabeter, Rotterdam, Netherlands.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mul, Dick
    Ctr Pediat & Adolescent Diabet Care & Res, Diabeter, Rotterdam, Netherlands.
    Martin, Frank
    JDRF, New York, NY USA.
    Boss, Marti
    Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, POB 9101, NL-6500 HB Nijmegen, Netherlands.
    Jansen, Tom J. P.
    Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, POB 9101, NL-6500 HB Nijmegen, Netherlands.
    van Lith, Sanne A. M.
    Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, POB 9101, NL-6500 HB Nijmegen, Netherlands.
    Buitinga, Mijke
    Univ Leuven, Clin & Expt Endocrinol, Leuven, Belgium.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Cnop, Miriam
    Univ Libre Bruxelles, Fac Med, ULB Ctr Diabet Res, Brussels, Belgium;Univ Libre Bruxelles, Erasmus Hosp, Div Endocrinol, Brussels, Belgium.
    Brom, Maarten
    Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, POB 9101, NL-6500 HB Nijmegen, Netherlands.
    Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 12, p. 2516-2519Article in journal (Refereed)
    Abstract [en]

    In this issue of Diabetologia, Alavi and Werner (10.1007/s00125-018-4676-1) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as futile'. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a futile' effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.

  • 265.
    Graae, Anne-Sofie
    et al.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark.
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.
    Ribel-Madsen, Rasmus
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark;Rigshosp, Dept Endocrinol, Copenhagen, Denmark;Novo Nordisk Fdn, Danish Diabet Acad, Odense, Denmark;Steno Diabet Ctr, Gentofte, Denmark.
    Lystbaek, Sara H.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark.
    Boesgaard, Trine
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.
    Staiger, Harald
    Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany;German Ctr Diabet Res, Tubingen, Germany;Eberhard Karls Univ Tubingen, Dept Pharm & Biochem, Inst Pharmaceut Sci, Tubingen, Germany.
    Fritsche, Andreas
    Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany;German Ctr Diabet Res, Tubingen, Germany;Univ Tubingen Hosp, Dept Internal Med 4, Tubingen, Germany.
    Wellner, Niels
    Aarhus Univ, Lundbeck Fdn Res Ctr MIND, Danish Res Inst Translat Neurosci, Nord EMBL Partnership Mol Med,Dept Biomed, Aarhus, Denmark.
    Sulek, Karolina
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark.
    Kjolby, Mads
    Novo Nordisk Fdn, Danish Diabet Acad, Odense, Denmark;Aarhus Univ, Lundbeck Fdn Res Ctr MIND, Danish Res Inst Translat Neurosci, Nord EMBL Partnership Mol Med,Dept Biomed, Aarhus, Denmark.
    Backe, Marie Balslev
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark.
    Chubanava, Sabina
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark.
    Prats, Clara
    Univ Copenhagen, Dept Biomed Sci, Ctr Hlth Aging, Xlab, Copenhagen, Denmark.
    Serup, Annette K.
    Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark.
    Birk, Jesper B.
    Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark.
    Dubail, Johanne
    Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44106 USA.
    Gillberg, Linn
    Steno Diabet Ctr, Gentofte, Denmark.
    Vienberg, Sara G.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark.
    Nykjaer, Anders
    Aarhus Univ, Lundbeck Fdn Res Ctr MIND, Danish Res Inst Translat Neurosci, Nord EMBL Partnership Mol Med,Dept Biomed, Aarhus, Denmark.
    Kiens, Bente
    Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark.
    Wojtaszewski, Jorgen F. P.
    Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark.
    Larsen, Steen
    Univ Copenhagen, Dept Biomed Sci, Ctr Hlth Aging, Xlab, Copenhagen, Denmark.
    Apte, Suneel S.
    Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44106 USA.
    Haering, Hans-Ulrich
    Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany;German Ctr Diabet Res, Tubingen, Germany;Univ Tubingen Hosp, Dept Internal Med 4, Tubingen, Germany.
    Vaag, Allan
    AstraZeneca, Cardiovasc & Metab Dis Translat Med Unit, Early Clin Dev Innovat Med & Early Dev Biotech Un, Gothenburg, Sweden.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.
    Treebak, Jonas T.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark.
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.
    Holst, Birgitte
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark.
    ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations2019In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 3, p. 502-514Article in journal (Refereed)
    Abstract [en]

    The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

  • 266.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Biochemical Testing in Patients with Neuroendocrine Tumors2015In: Neuroendocrine Tumors: A Multidisciplinary Approach / [ed] Papotti, M; DeHerder, WW, Krager , 2015, p. 24-39Chapter in book (Refereed)
    Abstract [en]

    Neuroendocrine tumors are usually slow-growing tumors. Many of these are capable of secreting peptide hormones or biogenic amines that may lead to endocrine syndromes. Nonfunctioning tumors can either secrete no hormones at all, or secrete hormones not giving rise to endocrine symptoms, such as chromogranin A, chromogranin B or pancreatic polypeptide. Chromogranin A is produced by the majority of endocrine tumors, both functioning and nonfunctioning, and is the best available marker for diagnosis, follow-up and treatment monitoring of patients with differentiated neuroendocrine tumors. Examples of endocrine syndromes are classical carcinoid syndrome caused by serotonin (measured in the urine as its metabolite 5-HIAA), insulinoma syndrome caused by insulin or proinsulin, Zollinger-Ellison syndrome resulting from gastrin secretion, glucagonoma syndrome caused by glucagon, WDHA syndrome caused by vasoactive intestinal peptide, or Cushing's syndrome resulting from ectopic production of adrenocorticotropic hormone or corticotropin-releasing hormone. In case there is uncertainty about the diagnosis, specific tests can be applied, such as the secretin test for diagnosis of gastrinomas and the 72-hour fast for diagnosis of an insulinoma. In patients with suspicion of an inherited syndrome, such as multiple endocrine neoplasia (MEN) 1 and MEN2 syndromes, genetic testing is indicated.

  • 267.
    Granström, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Patient-reported outcomes and visual acuity in patients after 12 months of anti-VEGF-treatment for sight-threatening diabetic macular edemaManuscript (preprint) (Other academic)
    Abstract [en]

    Aims: To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), and patient reported outcome measurements in patients treated with anti-VEGF treatment for visual impairment due to DME in routine clinical care after 12 months.

    Methods: In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68 years) with type 1 and type 2 diabetes diagnosed with macular edema were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used after anti-VEGF treatment.

    Results: Thirty patients had significantly improved visual acuity (p-value ˂ 0.001), and 27 patients had no improved visual acuity at 12 months. Both groups had significantly (p-value ˂ 0.001), reduced retinal thickness (OCT). The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health (p-value ˂ 0.004),, general vision (p-value - 0.001), near activities (p-value- 0.015), distance activities (p-value- 0.008), and composite score (p-value 0.024), but no significant changes in scores were found in the group without improvements in visual acuity.

    Conclusions: The patient-reported outcome measurements improved in the total patient population. A high HbA1c at baseline may be a risk factor for poor treatment effects.

  • 268.
    Granström, Therese
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden..
    Forsman, Henrietta
    Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden..
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Jani, Siba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Raghib, Aseel Modher
    Dalarna Cty Hosp, Dept Ophthalmol, Falun, Sweden..
    Granstam, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Department of Ophthalmology, Västmanland County Hospital, Västerås, Sweden.
    Visual functioning and health-related quality of life in diabetic patients about to undergo anti-vascular endothelial growth factor treatment for sight-threatening macular edema2015In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 29, no 8, p. 1183-1190Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine patient-reported outcome (PRO) in a selected group of Swedish patients about to receive anti-vascular endothelial growth factor (VEGF) treatment for diabetic macular edema (DME). Material and methods: In this cross-sectional study, 59 patients with diabetes mellitus, who regularly visited the outpatient eye-clinics, were included. Sociodemographic and clinical data were collected and the patients completed PRO measures before starting anti-VEGF treatment. PRO measures assessed eye-specific outcomes (NEI-VFQ-25) and generic health-related quality of life (SF-36). Results: The participants consisted of 30 men and 29 women (mean age, 68.5 years); 54 (92%) patients had type 2 diabetes; 5 (9%) patients had moderate or severe visual impairment; 28 (47%) were classified as having mild visual impairment. Some of the patients reported overall problems in their daily lives, such as with social relationships, as well as problems with impaired sight as a result of reduced distance vision. Conclusions: Further studies are needed to investigate PRO factors related to low perceived general health in this patient population. It is important to increase our understanding of such underlying mechanisms to promote improvements in the quality of patient care.

  • 269.
    Granström, Therese
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Forsman, Henrietta
    Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden..
    Olinder, Anna Lindholm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Söder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden.;Söder Sjukhuset, Karolinska Inst, Dept Clin Res & Educ, Stockholm, Sweden..
    Gkretsis, Dimitrios
    Dalarna Cty Hosp, Dept Ophthalmol, Falun, Sweden..
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Granstam, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Vastmanland Cty Hosp, Dept Ophthalmol, Vasteras, Sweden..
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Patient-reported outcomes and visual acuity after 12 months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting2016In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 121, p. 157-165Article in journal (Refereed)
    Abstract [en]

    Aims: To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), patient reported outcome and describe levels of glycated hemoglobin and its association with the effects on visual acuity in patients treated with anti-VEGF for visual impairment due to diabetic macular edema (DME) during 12 months in a real world setting.

    Methods: In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68 years) with type 1 and type 2 diabetes diagnosed with DME were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used.

    Results: The total patient group had significantly improved visual acuity and reduced retinal thickness at 4 months and remains at 12 months follow up. Thirty patients had significantly improved visual acuity, and 27 patients had no improved visual acuity at 12 months. The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health, general vision, near activities, distance activities, and composite score, but no significant changes in scores were found in the group without improvements in visual acuity.

    Conclusions: Our study revealed that anti-VEGF treatment improved visual acuity and central retinal thickness as well as patient-reported outcome in real world 12 months after treatment start.

  • 270.
    Grapensparr, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Zhanchun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Carlsson, Per-Ola
    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 Medical Sciences, Transplantation and regenerative medicine.
    Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed)
    Abstract [en]

    Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

  • 271. Grimaldi, Franco
    et al.
    Fazio, Nicola
    Attanasio, Roberto
    Frasoldati, Andrea
    Papini, Enrico
    Angelini, Francesco
    Baldelli, Roberto
    Berretti, Debora
    Bianchetti, Sara
    Bizzarri, Giancarlo
    Caputo, Marco
    Castello, Roberto
    Cremonini, Nadia
    Crescenzi, Anna
    Davi, Maria Vittoria
    D'Elia, Angela Valentina
    Faggiano, Antongiulio
    Pizzolitto, Stefano
    Versari, Annibale
    Zini, Michele
    Rindi, Guido
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms2014In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 37, no 9, p. 875-909Article in journal (Refereed)
  • 272.
    Groebe, Karlfried
    et al.
    Pivot Biomed Sci GmbH, D-54296 Trier, Germany.
    Cen, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schvartz, Domitille
    Univ Geneva, Ctr Med Univ, Human Prot Sci Dept, CH-1211 Geneva, Switzerland.
    Sargsyan, Ernest
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Chowdhury, Azazul Islam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Roomp, Kirsten
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, L-4365 Esch Sur Alzette, Luxembourg.
    Schneider, Reinhard
    Univ Luxembourg, Luxembourg Ctr Syst Biomed, L-4365 Esch Sur Alzette, Luxembourg.
    Alderborn, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sanchez, Jean-Charles
    Univ Geneva, Ctr Med Univ, Human Prot Sci Dept, CH-1211 Geneva, Switzerland.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palmitate-Induced Insulin Hypersecretion and Later Secretory Decline Associated with Changes in Protein Expression Patterns in Human Pancreatic Islets2018In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 11, p. 3824-3836Article in journal (Refereed)
    Abstract [en]

    In obese children with high circulating concentrations of free fatty acid palmitate, we have observed that insulin levels at fasting and in response to a glucose challenge were several times higher than in obese children with low concentrations of the fatty acid as well as in lean controls. Declining and even insufficient insulin levels were observed in obese adolescents with high levels of the fatty acid. In isolated human islets exposed to palmitate we have observed insulin hypersecretion after 2 days exposure. In contrast, insulin secretion from the islets was reduced after 7 days culture in the presence of the fatty acid. This study aims at identifying islet-related biological events potentially linked with the observed insulin hypersecretion and later secretory decline in these obese children and adolescents using the islet model. We analyzed protein expression data obtained from human islets exposed to elevated palmitate levels for 2 and 7 days by an improved methodology for statistical analysis of differentially expressed proteins. Protein profiling of islet samples by liquid chromatography-tandem mass spectrometry identified 115 differentially expressed proteins (DEPs). Several DEPs including sorcin were associated with increased glucose-stimulated insulin secretion in islets after 2 days of exposure to palmitate. Similarly, several metabolic pathways including altered protein degradation, increased autophagy, altered redox condition, and hampered insulin processing were coupled to the functional impairment of islets after 7 days of culture in the presence of palmitate. Such biological events, once validated in the islets, may give rise to novel treatment strategies aiming at normalizing insulin levels in obese children with high palmitate levels, which may reduce or even prevent obesity-related type 2 diabetes mellitus.

  • 273. Grouwels, G.
    et al.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Leuckx, G.
    Ngamjariyawat, Anongnad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Yuchi, Y.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Van de Casteele, M.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Heimberg, H.
    Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 7, p. 2016-2025Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    Efficient stimulation of cycling activity in cultured beta cells would allow the design of new strategies for cell therapy in diabetes. Neural crest stem cells (NCSCs) play a role in beta cell development and maturation and increase the beta cell number in co-transplants. The mechanism behind NCSC-induced beta cell proliferation and the functional capacity of the new beta cells is not known.

    Methods

    We developed a new in vitro co-culture system that enables the dissection of the elements that control the cellular interactions that lead to NCSC-dependent increase in islet beta cells.

    Results

    Mouse NCSCs were cultured in vitro, first in medium that stimulated their proliferation, then under conditions that supported their differentiation. When mouse islet cells were cultured together with the NCSCs, more than 35% of the beta cells showed cycle activity. This labelling index is more than tenfold higher than control islets cultured without NCSCs. Beta cells that proliferated under these culture conditions were fully glucose responsive in terms of insulin secretion. NCSCs also induced beta cell proliferation in islets isolated from 1-year-old mice, but not in dissociated islet cells isolated from human donor pancreas tissue. To stimulate beta cell proliferation, NCSCs need to be in intimate contact with the beta cells.

    Conclusions/interpretation

    Culture of islet cells in contact with NCSCs induces highly efficient beta cell proliferation. The reported culture system is an excellent platform for further dissection of the minimal set of factors needed to drive this process and explore its potential for translation to diabetes therapy.

  • 274.
    Grönberg, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Swenne, Ingemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Recovery of premorbid BMI trajectory without overshoot during the first year of treatment of children with type 1 diabetes2016In: BMJ Open Diabetes Research & Care, ISSN 2052-4897, Vol. 4, no 1, article id e000209Article in journal (Refereed)
  • 275. Gudbjörnsdottir, S
    et al.
    Eliasson, B
    Eeg-Olofsson, K
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Additive effects of glycaemia and dyslipidaemia on risk of cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register2011In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 10, p. 2544-2551Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    The study aimed to assess the relative importance of the control of HbA(1c) and total cholesterol/HDL-cholesterol ratio (TC/HDL) on risk of cardiovascular disease (CVD).

    METHODS:

    In 22,135 participants with type 2 diabetes (age 30-75 years, 15% with previous CVD) followed for 5 years, baseline and annually updated mean HbA(1c) and TC/HDL were analysed and also categorised in combinations of quartiles. Outcomes were fatal/non-fatal CHD, stroke, CVD and total mortality.

    RESULTS:

    In all participants, HRs per 1 SD increase in updated mean HbA(1c) or TC/HDL using Cox regression analysis were 1.13 (95% CI 1.07, 1.19) and 1.31 (1.25, 1.37) for CHD, 1.15 (1.06, 1.24) and 1.25 (1.17, 1.34) for stroke, 1.13 (1.08, 1.18) and 1.29 (1.24, 1.34) for CVD (all p < 0.001), and 1.07 (1.02, 1-13; p = 0.01) and 1.18 (1.12, 1.24; p < 0.001) for total mortality, respectively, adjusted for clinical characteristics and traditional risk factors. The p value for the interaction between HbA(1c) and TC/HDL was 0.02 for CHD, 0.6 for stroke and 0.1 for CVD. Adjusted mean 5-year event rates in a Cox model, in combinations of quartiles of updated mean TC/HDL and HbA(1c) (lowest <3.1 mmol/l and 5.0-6.4% [31-46 mmol/mol]; <3.1 mmol/l and ≥7.8% [≥62 mmol/mol]; ≥4.6 mmol/l and 5.0-6.4% 31-46 mmol/mol; and highest ≥4.6 mmol/l and ≥7.8% [≥62 mmol/mol]), were 4.8%, 7.0%, 9.1% and 14.5% for CHD, and 7.1%, 9.9%, 12.8% and 19.4% for CVD, respectively. Adjusted HRs for highest vs lowest combinations were 2.24 (1.58-3.18) for CHD and 2.43 (1.79-3.29) for CVD (p < 0.001).

    CONCLUSIONS/INTERPRETATION:

    Hyperglycaemia and hyperlipidaemia were less than additive for CHD and additive for other endpoints, with the lowest risk at lowest combination levels and a considerable increase in absolute risk at high combination levels.

  • 276.
    Gulseth, Hanne L.
    et al.
    Univ Oslo, Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway;Norwegian Inst Publ Hlth, Dept Chron Dis & Ageing, Oslo, Norway.
    Gjelstad, Ingrid M. F.
    Univ Oslo, Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway.
    Tiereny, Audrey C.
    Univ Coll Dublin, UCD Conway Inst, Nutrigen Res Grp, Dublin, Ireland;Univ Coll Dublin, UCD Inst Food & Hlth, Sch Publ Hlth Physiotherapy & Sports Sci, Dublin, Ireland;Univ Limerick, Sch Allied Hlth, Limerick, Ireland;La Trobe Univ, Sch Allied Hlth, Melbourne, Vic, Australia.
    McCarthy, Danielle
    Univ Reading, Dept Food Biosci, Hugh Sinclair Unit Human Nutr, Reading, Berks, England;Queens Univ Belfast, Northern Ireland Technol Ctr, Inst Global Food Secur, Belfast, Antrim, North Ireland.
    Lovegrove, Julie A.
    Univ Reading, Dept Food Biosci, Hugh Sinclair Unit Human Nutr, Reading, Berks, England;Univ Reading, Inst Cardiovasc & Metab Res, Reading, Berks, England.
    Defoort, Catherine
    Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France.
    Blaak, Ellen E.
    Maastricht Univ, Med Ctr, Sch Nutr Toxicol & Metab, NUTRIM, Maastricht, Netherlands.
    Lopez-Miranda, Jose
    Univ Cordoba, Hosp Univ Reina Sofia, Inst Maimonides Invest Biomed Cordoba IMIBIC, Lipids & Atherosclerosis Res Unit, Madrid, Spain;Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr CIBEROBN, Madrid, Spain.
    Dembinska-Kiec, Aldona
    Jagiellonian Univ, Dept Clin Biochem, Med Coll, Krakow, Poland.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Roche, Helen M.
    Univ Coll Dublin, UCD Conway Inst, Nutrigen Res Grp, Dublin, Ireland;Univ Coll Dublin, UCD Inst Food & Hlth, Sch Publ Hlth Physiotherapy & Sports Sci, Dublin, Ireland.
    Drevon, Christian A.
    Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway.
    Birkeland, Kare, I
    Univ Oslo, Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
    Effects of dietary fat on insulin secretion in subjects with the metabolic syndrome2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 180, no 5, p. 321-328Article in journal (Refereed)
    Abstract [en]

    Objective: Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome.

    Design: In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test.

    Results: There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the highfat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010).

    Conclusions: The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

  • 277.
    Gylfe, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Neurotransmitter control of islet hormone pulsatility2014In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, no S1, p. 102-110Article, review/survey (Refereed)
    Abstract [en]

    Pulsatile secretion is an inherent property of hormone-releasing pancreatic islet cells. This secretory pattern is physiologically important and compromised in diabetes. Neurotransmitters released from islet cells may shape the pulses in auto/paracrine feedback loops. Within islets, glucose-stimulated -cells couple via gap junctions to generate synchronized insulin pulses. In contrast, - and -cells lack gap junctions, and glucagon release from islets stimulated by lack of glucose is non-pulsatile. Increasing glucose concentrations gradually inhibit glucagon secretion by -cell-intrinsic mechanism/s. Further glucose elevation will stimulate pulsatile insulin release and co-secretion of neurotransmitters. Excitatory ATP may synchronize -cells with -cells to generate coinciding pulses of insulin and somatostatin. Inhibitory neurotransmitters from - and -cells can then generate antiphase pulses of glucagon release. Neurotransmitters released from intrapancreatic ganglia are required to synchronize -cells between islets to coordinate insulin pulsatility from the entire pancreas, whereas paracrine intra-islet effects still suffice to explain coordinated pulsatile release of glucagon and somatostatin. The present review discusses how neurotransmitters contribute to the pulsatility at different levels of integration.

  • 278.
    Hadrévi, Jenny
    et al.
    Umeå Univ, Dept Publ Hlth & Clin Med, Occupat & Environm Med, Umeå, Sweden.
    Jonsdottir, Ingibjorg H.
    Inst Stress Med, Gothenburg, Region Västra Götaland, Sweden; Univ Gothenburg, Dept Food & Nutr & Sport Sci, Gothenburg, Sweden.
    Jansson, Per-Anders
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sjörs, Anna
    Inst Stress Med, Gothenburg, Region Västra Götaland, Sweden; Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci & Rehabil, Gothenburg, Sweden.
    Plasma metabolomic patterns in patients with exhaustion disorder2019In: Stress, ISSN 1025-3890, E-ISSN 1607-8888, Vol. 22, no 1, p. 17-26Article in journal (Refereed)
    Abstract [en]

    Exhaustion disorder (ED) is a stress-related disorder that often implies a great burden on the individual patient as well as on society. Previous studies have shown that ED is associated with metabolic deviations, such as lowered fasting glucose. Several mechanisms have been discussed as a plausible explanation of the lack of energy described by these patients. Metabolic processes and reduced ability to mobilize energy have been suggested as important factors. This study investigated metabolomics in 20 patients diagnosed with ED and compared them with 21 healthy controls. Plasma metabolic profiles were examined in both fasting and nonfasting (postprandial) conditions. Blood plasma samples were analyzed for metabolite content using gas chromatography mass spectrometry. A total of 62 different metabolites were simultaneously detected in each of the samples. Multivariate models indicated systematic differences between patients with ED and healthy controls in both their fasting and nonfasting plasma metabolite levels. Lysine and octadecenoic acid were more abundant and glutamine, glycine, serine and gluconic acid were less abundant in the patients across both conditions. In the present study, we comprehensively and simultaneously screen for changes in a large number of metabolites. Our results show a difference in systemic metabolites between patients with exhaustion disorder and healthy controls both in the fasting and in the postprandial states. Here, we present new potential biomarkers mirroring exhaustion disorder metabolism.Lay summary Exhaustion disorder (ED) patients suffer from stress-related symptoms including a reduced energy level. This study investigates the body's metabolism in patients with ED, both fasting and after a meal. New potential markers that may help future investigations on ED were identified.

  • 279.
    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.

  • 280.
    Halford, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Jonsdottír, Ingibjörg H.
    Eek, Frida
    Perceived stress, psychological resources and salivary cortisol2012In: The role of saliva cortisol measurement in health and disease / [ed] Kristenson M, Garvin P, Lundberg U, Bentham eBooks, 2012, p. 67-86Chapter in book (Refereed)
    Abstract [en]

    The aim of this chapter was to analyze associations between measures of cortisol in saliva with measures of perceived stress, using the Perceived Stress Scale (PSS), and of psychological resources in terms of mastery, locus of control, self-esteem and sense of coherence. Only studies on healthy individuals were included and cortisol measures were grouped into single time point measures, deviation measures, Area Under the Curve (AUC), laboratory test responses, and dexamethasone suppression. For both Perceived Stress Scale (PSS) and for psychological resources, most results of associations with saliva cortisol were nonsignificant particularly for single measures and for cortisol awakening response. For PSS the largest proportion of significant findings (38%) was seen for morning AUC, however with conflicting results. For psychological resource constructs, mastery and sense of coherence were related to lower cortisol level at baseline in standardized rest and high mastery was related to steeper diurnal slope in two studies. For self-esteem, no associations showed significant results. Differences in findings may to a large extent be dependent on theoretical assumptions made and methods used.

  • 281.
    Halin Lejonklou, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    The MEN 1 Pancreas: Tumor Development and Haploinsufficiency2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the MEN1 gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both MEN1 alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The MEN1 protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization.

    We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas.

    Notch signaling factor expression and localization were examined in the pancreas of a heterozygous Men1 mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that Notch1 was less expressed in heterozygous islets compared to wild-type islets.

    Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous Men1 mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and in situ PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals.

    It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.

    List of papers
    1. Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells
    Open this publication in new window or tab >>Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells
    Show others...
    2009 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 38, no 3, p. 259-266Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.

    METHODS:

    The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.

    RESULTS:

    Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.

    CONCLUSIONS:

    Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.

    Keywords
    MEN1, pancreas, transcription factors, subcellular localization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-110616 (URN)10.1097/MPA.0b013e3181930818 (DOI)000264763400004 ()19307926 (PubMedID)
    Available from: 2009-11-18 Created: 2009-11-18 Last updated: 2017-12-12Bibliographically approved
    2. Notch signaling factors in the transforming Men1 mouse pancreas
    Open this publication in new window or tab >>Notch signaling factors in the transforming Men1 mouse pancreas
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-177595 (URN)
    Available from: 2012-07-16 Created: 2012-07-16 Last updated: 2018-06-04
    3. Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor
    Open this publication in new window or tab >>Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor
    2012 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 6, p. 2588-2598Article in journal (Refereed) Published
    Abstract [en]

    Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. Wild-type littermates were used for comparison. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. 1.74%; P = 0.024). The microarray results demonstrated that several genes were differentially expressed. Some selected genes were studied on the protein level, e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate (Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting (P < 0.001 and P < 0.01, respectively). Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. chromatin maintenance and apoptosis. Lower mRNA was observed for genes involved in growth factor binding. In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-174062 (URN)10.1210/en.2011-1924 (DOI)000304370700011 ()22492302 (PubMedID)
    Available from: 2012-05-10 Created: 2012-05-10 Last updated: 2017-12-07Bibliographically approved
    4. Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
    Open this publication in new window or tab >>Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
    2012 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 6, p. 1411-1418Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated.

    METHODS:

    A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed.

    RESULTS:

    Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90).

    CONCLUSIONS:

    High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-162584 (URN)10.1007/s00268-011-1345-7 (DOI)000304096800030 ()22089920 (PubMedID)
    Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2017-12-08Bibliographically approved
  • 282.
    Hanson, Linda L. Magnusson
    et al.
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden.
    Virtanen, Marianna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Public Health. Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden.
    Rod, Naja H.
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden;Univ Copenhagen, Dept Publ Hlth, Sect Epidemiol, Copenhagen, Denmark.
    Steptoe, Andrew
    UCL, Res Dept Behav Sci & Hlth, London, England.
    Head, Jenny
    UCL, Dept Epidemiol & Publ Hlth, London, England.
    Batty, G. D.
    UCL, Dept Epidemiol & Publ Hlth, London, England.
    Kivimäki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London, England;Univ Helsinki, Fac Med, Clinicum, Helsinki, Finland.
    Westerlund, Hugo
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden.
    Does inflammation provide a link between psychosocial work characteristics and diabetes?: Analysis of the role of interleukin-6 and C-reactive protein in the Whitehall II cohort study2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 78, p. 153-160Article in journal (Refereed)
    Abstract [en]

    Objective: Inflammation may underlie the association between psychological stress and cardiometabolic diseases, but this proposition has not been tested longitudinally. We investigated whether the circulating inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) mediate the relationship between psychosocial work characteristics and diabetes.

    Methods: We used three phases of data at 5 years intervals from the Whitehall II cohort study, originally recruiting 10,308 civil service employees aged 35-55 years. The data included repeat self-reports of job demands, control and social support, IL-6 from plasma samples, CRP from serum samples, and diabetes, ascertained through oral glucose tolerance test, medications, and self-reports of doctor-diagnosed diabetes.

    Results: Structural equation models with age, sex and occupational position considering men and women combined, showed that low social support at work, but not high job demands or low job control, was prospectively associated with diabetes (standardized beta = 0.05, 95% confidence interval (CI) 0.01-0.09) and higher levels of IL-6 (beta = 0.03, CI 0.00-0.06). The inflammatory markers and diabetes were bidirectionally associated over time. A mediation model including workplace social support, IL-6 and diabetes further showed that 10% of the association between social support and diabetes over the three repeat examinations (total effect beta = 0.08, CI 0.01-0.15) was attributable to a weak indirect effect through IL-6 (beta = 0.01, CI 0.00-0.02). A similar indirect effect was observed for CRP in men only, while job control was prospectively associated with IL-6 among women.

    Conclusions: This study indicates an association between poor workplace support and diabetes that is partially ascribed to an inflammatory response.

  • 283.
    Hansson, S. F.
    et al.
    AstraZeneca, R&D Molndal, Translat Sci, Molndal, Sweden..
    Vachet, P.
    AstraZeneca, R&D Molndal, Translat Sci, Molndal, Sweden..
    Hammar, M.
    AstraZeneca, R&D Molndal, Translat Sci, Molndal, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Davidsson, P.
    AstraZeneca, R&D Molndal, Translat Sci, Molndal, Sweden..
    Identification of potential circulating beta cell biomarkers2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S149-S150Article in journal (Other academic)
  • 284.
    Hansson, Tony
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Dahlbom, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Tuvemo, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings2015In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no 2, p. 185-191Article in journal (Refereed)
    Abstract [en]

    AimThis study measured autoantibodies against tissue transglutaminase (anti-tTG) to detect untreated coeliac disease in children with type 1 diabetes and their siblings. MethodsAnti-tTG was measured in prospectively collected sera from 169 children at the onset of diabetes, 88 of their siblings and 96 matched control children. Coeliac disease was confirmed with a small intestinal biopsy. ResultsCoeliac disease was diagnosed in five children before diabetes onset. A further 12 children were diagnosed after diabetes onset, without any gastrointestinal symptoms, and 11 of these had anti-tTG at the onset of diabetes, with the remaining child showing seroconversion within 6months. Hence, all the children with both diseases had anti-tTG at or before diabetes diagnosis, and the prevalence of coeliac disease was 10.1%. Moreover, 6.8% of the siblings and 3.1% of the control children had elevated levels of anti-tTG. None of the siblings reported any coeliac-related symptoms, despite being positive for anti-tTG, and coeliac disease has so far been biopsy confirmed in 4.5%. ConclusionSilent coeliac disease is over-represented in children with type 1 diabetes and their siblings. All diabetes children and their siblings should be tested and followed for the presence of anti-tTG and coeliac disease.

  • 285.
    Harati, Hadi
    et al.
    Stanford Univ, Sch Med, Dept Med, Div Endocrinol, Stanford, CA USA.
    Zanetti, Daniela
    Stanford Univ, Falk Cardiovasc Res Ctr, Div Cardiovasc Med, Dept Med,Sch Med, 300 Pasteur Dr,CV 273, Stanford, CA 94305 USA.
    Rao, Abhiram
    Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Perez, Marco
    Stanford Univ, Falk Cardiovasc Res Ctr, Div Cardiovasc Med, Dept Med,Sch Med, 300 Pasteur Dr,CV 273, Stanford, CA 94305 USA.
    Ingelsson, Erik
    Stanford Univ, Falk Cardiovasc Res Ctr, Div Cardiovasc Med, Dept Med,Sch Med, 300 Pasteur Dr,CV 273, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA.
    Knowles, Joshua W.
    Stanford Univ, Falk Cardiovasc Res Ctr, Div Cardiovasc Med, Dept Med,Sch Med, 300 Pasteur Dr,CV 273, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA.
    No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 5, p. 800-804Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.

    Methods

    Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA(1c) on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.

    Results

    Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p=0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p=0.49) or HbA(1c) (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p=0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA(1c), respectively, for associations with atrial fibrillation.

    Conclusions/interpretation

    This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA(1c) and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.

  • 286.
    Harvey, N. C.
    et al.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Tremona Rd, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Tremona Rd, Southampton, Hants, England..
    Johansson, H.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden.;Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Oden, A.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden.;Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Karlsson, M. K.
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Rosengren, B. E.
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Tremona Rd, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Tremona Rd, Southampton, Hants, England.;Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Oxford, England..
    McCloskey, E.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    FRAX predicts incident falls in elderly men: findings from MrOs Sweden2016In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, no 1, p. 267-274Article in journal (Refereed)
    Abstract [en]

    A Summary Falls and fractures share several common risk factors. Although past falls is not included as an input variable in the FRAX calculator, we demonstrate that FRAX probability predicts risk of incident falls in the MrOs Sweden cohort. Introduction Although not included in the FRAXA (R) algorithm, it is possible that increased falls risk is partly dependent on other risk factors that are incorporated into FRAX. The aim of the present study was to determine whether fracture probability generated by FRAX might also predict risk of incident falls and the extent that a falls history would add value to FRAX. Methods We studied the relationship between FRAX probabilities and risk of falls in 1836 elderly men recruited to the MrOS study, a population-based prospective cohort of men from Sweden. Baseline data included falls history, clinical risk factors, bone mineral density (BMD) at femoral neck, and calculated FRAX probabilities. Incident falls were captured during an average of 1.8 years of follow-up. An extension of Poisson regression was used to investigate the relationship between FRAX, other risk variables, and the time-to-event hazard function of falls. All associations were adjusted for age and time since baseline. Results At enrolment, 15.5 % of the men had fallen during the preceding 12 months (past falls) and 39 % experienced one or more falls during follow-up (incident falls). The risk of incident falls increased with increasing FRAX probabilities at baseline (hazard ratio (HR) per standard deviation (SD), 1.16; 95 % confidence interval (95%CI), 1.06 to 1.26). The association between incident falls and FRAX probability remained after adjustment for past falls (HR per SD, 1.12; 95%CI, 1.03 to 1.22). High compared with low baseline FRAX score (>15 vs <15 % probability of major osteoporotic fracture) was strongly predictive of increased falls risk (HR, 1.64; 95%CI, 1.36 to 1.97) and remained stable with time. Whereas past falls were a significant predictor of incident falls (HR, 2.75; 95%CI, 2.32 to 3.25), even after adjustment for FRAX, the hazard ratio decreased markedly with increasing follow-up time. Conclusions Although falls are not included as an input variable, FRAX captures a component of risk for future falls and outperforms falls history with an extended follow-up time.

  • 287.
    Harvey, N. C.
    et al.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    Johansson, H.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Karlsson, M. K.
    Lund Univ, Skane Univ Hosp, Clin & Mol Osteoporosis Res Unit, Dept Orthoped & Clin Sci, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Skane Univ Hosp, Clin & Mol Osteoporosis Res Unit, Dept Orthoped & Clin Sci, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    The Predictive Value Of Past Falls For Incident Falls Decreases, But That Of Frax Remains Stable, With Increasing Follow-Up Time: Findings From MROS Sweden2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, p. S143-S143Article in journal (Other academic)
  • 288.
    Harvey, N. C.
    et al.
    Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Botnar Res Ctr, Oxford, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    Orwoll, E.
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Lapidus, J.
    Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Div Biostat, Portland, OR 97201 USA..
    Kwok, T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China..
    Karlsson, M.
    Lund Univ, Dept Orthopaed & Clin Sci, Skane Univ Hosp, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Botnar Res Ctr, Oxford, England..
    Kanis, J. A.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenberg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Johansson, H.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    Mobility Related Risk Factors Predict Incident Fractures Independently Of Frax: The Osteoporotic Fractures In Men (MROS) Study2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S61-S61Article in journal (Other academic)
  • 289.
    Harvey, N. C.
    et al.
    Univ Oxford, Musculoskeletal Epidemiol, Botnar Res Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England..
    Oden, A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Orwoll, E.
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Lapidus, J.
    Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Div Biostat, Portland, OR 97201 USA..
    Kwok, T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China..
    Karlsson, M.
    Lund Univ, Dept Orthopaed & Clin Sci, Skane Univ Hosp, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Oxford, Musculoskeletal Epidemiol, Botnar Res Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England..
    McCloskey, E.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenberg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Johansson, H.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    PRIOR FALLS PREDICT INCIDENT FRACTURES INDEPENDENTLY OF FRAX: The Osteoporotic Fractures In Men (MROS) Study2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S259-S259Article in journal (Other academic)
  • 290.
    Harvey, Nicholas C.
    et al.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England..
    Oden, Anders
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden.;Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Orwoll, Eric
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Lapidus, Jodi
    Oregon Hlth & Sci Univ, Div Biostat, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA..
    Kwok, Timothy
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China..
    Karlsson, Magnus K.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Rosengren, Björn E.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, Cyrus
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Oxford, England..
    McCloskey, Eugene
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England.;Univ Sheffield, Ctr Integrated Res Musculoskeletal Ageing CIMA, Mellanby Ctr Bone Res, Sheffield, S Yorkshire, England..
    Kanis, John A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England.;Catholic Univ Australia, Inst Hlth & Aging, Melbourne, Vic, Australia..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Mellström, Dan
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Johansson, Helena
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden.;Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England.;Catholic Univ Australia, Inst Hlth & Aging, Melbourne, Vic, Australia..
    Falls Predict Fractures Independently of FRAX Probability: A Meta-Analysis of the Osteoporotic Fractures in Men (MrOS) Study2018In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 3, p. 510-516Article in journal (Refereed)
    Abstract [en]

    Although prior falls are a well-established predictor of future fracture, there is currently limited evidence regarding the specific value of falls history in fracture risk assessment relative to that of other clinical risk factors and bone mineral density (BMD) measurement. We therefore investigated, across the three Osteoporotic Fractures in Men (MrOS) Study cohorts, whether past falls predicted future fracture independently of FRAX and whether these associations varied with age and follow-up time. Elderly men were recruited from MrOS Sweden, Hong Kong, and USA. Baseline data included falls history (over the preceding 12 months), clinical risk factors, BMD at femoral neck, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the associations between falls, FRAX probability, and incident fracture, adjusting for age, time since baseline, and cohort in base models; further models were used to investigate interactions with age and follow-up time. Random-effects meta-analysis was used to synthesize the individual country associations. Information on falls and FRAX probability was available for 4365 men in USA (mean age 73.5 years; mean follow-up 10.8 years), 1823 men in Sweden (mean age 75.4 years; mean follow-up 8.7 years), and 1669 men in Hong Kong (mean age 72.4 years; mean follow-up 9.8 years). Rates of past falls were similar at 20%, 16%, and 15%, respectively. Across all cohorts, past falls predicted incident fracture at any site (hazard ratio [HR]=1.69; 95% confidence interval [CI] 1.49, 1.90), major osteoporotic fracture (MOF) (HR=1.56; 95% CI 1.33, 1.83), and hip fracture (HR=1.61; 95% CI 1.27, 2.05). Relationships between past falls and incident fracture remained robust after adjustment for FRAX probability: adjusted HR (95% CI) any fracture: 1.63 (1.45, 1.83); MOF: 1.51 (1.32, 1.73); and hip: 1.54 (1.21, 1.95). In conclusion, past falls predicted incident fracture independently of FRAX probability, confirming the potential value of falls history in fracture risk assessment.

  • 291.
    Harvey, Nicholas
    et al.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants.
    Oden, Anders
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg.
    Orwoll, Eric
    Oregon Hlth & Sci Univ, Portland.
    Lapidus, Jodi
    Oregon Hlth & Sci Univ, Div Biostat, Dept Publ Hlth & Prevent Med, Portland.
    Kwok, Timothy
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong.; Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong.
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Lund.; Skåne Univ Hosp, Dept Orthoped, Lund.
    Rosengren, Bjorn
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Lund.; Skåne Univ Hosp, Dept Orthoped, Lund.
    Ljunggren, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cooper, Cyrus
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants.
    Cawthon, Peggy
    Univ Calif, Dept Epidemiol & Biostat, Oakland.
    Kanis, John
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg.
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg.
    Johansson, Helena
    Catholic Univ Australia, Inst Hlth & Aging, Sydney, NSW.
    McCloskey, Eugene
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire.
    Measures of physical performance or function, but not appendicular lean mass, predict new fractures independently of FRAX probability: Findings from MrOS2017In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, no S1, p. S30-S30, article id Meeting Abstract: 1085Article in journal (Other academic)
  • 292.
    Hawinkels, Lukas J A C
    et al.
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Exploring anti-TGF-β therapies in cancer and fibrosis2011In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 29, no 4, p. 140-152Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-β (TGF-β) is a multifunctional cytokine, with important roles in maintaining tissue homeostasis. TGF-β signals via transmembrane serine/threonine kinase receptors and intracellular Smad transcriptional regulators. Perturbed TGF-β signaling has been implicated in a large variety of pathological conditions. Increased TGF-β levels have been found in patients with cancer, fibrosis, and systemic sclerosis, and were correlated with disease severity. In cancer, TGF-β mediates tumor invasion and metastasis by affecting both tumor cells and the tumor microenvironment including fibroblast activation and immune suppression. Furthermore, TGF-β is a strong stimulator of extracellular matrix deposition. On the basis of these observations, small molecule inhibitors of the TGF-β receptor kinases, neutralizing antibodies that interfere with ligand?receptor interactions, antisense oligonucleotides reducing TGF-β expression, and soluble receptor ectodomains that sequester TGF-β have been developed to intervene with excessive TGF-β signaling activity in the aforementioned disorders. Here, we review the current state of anti-TGF-β therapy in clinical trials.

  • 293.
    Heany, Sarah J.
    et al.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa..
    van Honk, Jack
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa.;Univ Utrecht, Dept Psychol, Utrecht, Netherlands.;Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa..
    Stein, Dan J.
    Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa..
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Cape Town, Groote Schuur Hosp, Dept Psychiat & Mental Hlth, J2,Anzio Rd, ZA-7925 Cape Town, South Africa..
    A quantitative and qualitative review of the effects of testosterone on the function and structure of the human social-emotional brain2016In: Metabolic brain disease, ISSN 0885-7490, E-ISSN 1573-7365, Vol. 31, no 1, p. 157-167Article in journal (Refereed)
    Abstract [en]

    Social and affective research in humans is increasingly using functional and structural neuroimaging techniques to aid the understanding of how hormones, such as testosterone, modulate a wide range of psychological processes. We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies of testosterone administration, and of fMRI studies that measured endogenous levels of the hormone, in relation to social and affective stimuli. Furthermore, we conducted a review of structural MRI i.e. voxel based morphometry (VBM) studies which considered brain volume in relation to testosterone levels in adults and in children. In the included testosterone administration fMRI studies, which consisted of female samples only, bilateral amygdala/parahippocampal regions as well as the right caudate were significantly activated by social-affective stimuli in the testosterone condition. In the studies considering endogenous levels of testosterone, stimuli-invoked activations relating to testosterone levels were noted in the bilateral amygdala/parahippocampal regions and the brainstem. When the endogenous testosterone studies were split by sex, the significant activation of the brain stem was seen in the female samples only. Significant stimuli-invoked deactivations relating to endogenous testosterone levels were also seen in the right and left amygdala/parahippocampal regions studies. The findings of the VBM studies were less consistent. In adults larger volumes in the limbic and temporal regions were associated with higher endogenous testosterone. In children, boys showed a positive correlation between testosterone and brain volume in many regions, including the amygdala, as well as global grey matter volume, while girls showed a neutral or negative association between testosterone levels and many brain volumes. In conclusion, amygdalar and parahippocampal regions appear to be key target regions for the acute actions of testosterone in response to social and affective stimuli, while neurodevelopmentally the volumes of a broader network of brain structures are associated with testosterone levels in a sexually dimorphic manner.

  • 294. Heck, Ansgar
    et al.
    Emblem, Kyrre E
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bollerslev, Jens
    Ringstad, Geir
    Quantitative analyses of T2-weighted MRI as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly2016In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 52, no 2, p. 333-343Article in journal (Refereed)
    Abstract [en]

    In growth hormone (GH)-producing adenomas, T2-weighted MRI signal intensity is a marker for granulation pattern and response to somatostatin analogs (SSA). Prediction of treatment response is necessary for individualized treatment, and T2 intensity assessment might improve preoperative classification of somatotropinomas. The objectives of this study are (I) to explore the feasibility of quantitative T2-weighted MRI histogram analyses in newly diagnosed somatotroph adenomas and their relation to clinical and histological parameters and (II) to compare the quantitative method to conventional, visual assessment of T2 intensity. The study was a retrospective cohort study of 58 newly diagnosed patients. In 34 of these, response to primary SSA treatment after median 6 months was evaluated. Parameters from the T2 histogram analyses (T2 intensity ratio and T2 homogeneity ratio) were correlated to visually assessed T2 intensity (hypo-, iso-, hyperintense), baseline characteristics, response to SSA treatment, and histological granulation pattern (anti-Cam5.2). T2 intensity ratio was lowest in the hypointense tumors and highest in the hyperintense tumors (0.66 ± 0.10 vs. 1.07 ± 0.11; p < 0.001). T2 intensity at baseline correlated with reduction in GH (r = -0.67; p < 0.001) and IGF-1 (r = -0.36; p = 0.037) after primary SSA treatment (n = 34). The T2 homogeneity ratio correlated with adenoma size reduction (r = -0.45; p = 0.008). Sparsely granulated adenomas had a higher T2 intensity than densely or intermediately granulated adenomas. T2 histogram analyses are an applicable tool to assess T2 intensity in somatotroph adenomas. Quantitatively assessed T2 intensity ratio in GH-producing adenomas correlates with conventional assessment of T2 intensity, baseline characteristics, response to SSA treatment, and histological granulation pattern.

  • 295. Heck, Ansgar
    et al.
    Emblem, Kyrre E
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ringstad, Geir
    Bollerslev, Jens
    MRI T2 characteristics in somatotroph adenomas following somatostatin analog treatment in acromegaly2016In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 53, no 1, p. 327-330Article in journal (Refereed)
  • 296. Hellgren, G.
    et al.
    Glad, C. A.
    Jonsson, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Johannsson, G.
    Albertsson-Wikland, K.
    The growth hormone receptor exon 3-deleted/full-length polymorphism and response to growth hormone therapy in prepubertal idiopathic short children2015In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 25, no 3, p. 127-135Article in journal (Refereed)
    Abstract [en]

    Objective: The primary aim of the study was to evaluate d3-GHR as a possible cause of increased GH sensitivity in children with delayed infancy-childhood transition (DICT). The secondary aim was to investigate the impact of the GHR exon 3 deleted/full-length (d3/f1) polymorphism on GH treatment response in prepubertal children classified as having idiopathic short stature (ISS). Design: Study subjects included 167 prepubescent longitudinally followed children classified as having ISS. Children were randomized to standard-dose GH treatment (33 mu g kg(-1) day(-1)), to double-dose treatment (67 mu g kg(-1) day(-1)), or to an untreated control group. Growth and metabolic outcome were evaluated at birth (n = 166), after one year of treatment (n = 59) and at adult height (n = 145). Genotyping of the GHR d3/f1 polymorphism was performed using TaqMan SNP genotyping of tagSNP rs6873545. Results: Birth and early growth data did not reach the predetermined level of statistical significance for difference between genotypes. Growth and IGF-1 response after one year of GH treatment did not differ between genotypes. IGFBP-3(SDS) was higher in untreated d3-GHR carriers than in untreated fl/fl individuals, whereas there was insufficient evidence for higher IGFBP-3(SDS) in treated d3-GHR carriers. Genotype did not explain the growth response to treatment, and no differences in height(SDS), height gain, or difference in height to midparental height(SDS) between genotype groups were found at adult height. Conclusion: The common GHR d3/fl polymorphism is probably not a cause of DICT in children with ISS, and our results do not suggest that the d3-GHR genotype is associated with increased sensitivity to GH in children with ISS.

  • 297.
    Hellman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dansk, Heléne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapengiesser, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Somatostatin promotes glucose generation of Ca2+ oscillations in pancreatic islets both in the absence and presence of tolbutamide2018In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 74, p. 35-42Article in journal (Refereed)
    Abstract [en]

    Many cellular processes, including pulsatile release of insulin, are triggered by increase of cytoplasmic Ca2+. This study examines how somatostatin affects glucose generation of cytoplasmic Ca2+ oscillations in mouse islets in absence and presence of tolbutamide blockade of the K-ATP channels. Ca2+ was measured with dual wavelength microflurometry in isolated islets loaded with the indicator Fura-2. Rise of glucose from 3 to 20 mM evoked introductory lowering of Ca2+ prolonged by activation of somatostatin receptors. During continued superfusion exposure to somatostatin triggered oscillations mediated by periodic increase from the basal level (absence of tolbutamide) or by periodic interruption of an elevated level (presence of tolbutamide). In the latter situation the oscillations were transformed into sustained elevation by activation of muscarinic receptors (acetylcholine) or increase of cyclic AMP (IBMX, 8-bromo-cyclic AMP, forskolin). The observed effect of cyclic AMP raises the question whether high proportions of the glucagon-producing alpha-cells promote steady-state elevation of Ca2+. In support for this idea somatostatin was found to trigger glucose-induced Ca2+ oscillations essentially in small islets that contain very few alpha-cells. The results indicate that somatostatin promotes glucose generation of Ca2+ oscillations with similar characteristics both in the absence and presence of functional K-ATP channels.

  • 298.
    Hellström-Lindahl, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Danielsson, Angelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Czernichow, Paul
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    GPR44 is a pancreatic protein restricted to the human beta cell2016In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 53, no 3, p. 413-421Article in journal (Refereed)
    Abstract [en]

    AIMS: To address questions regarding onset and progression of types 1 and 2 diabetes (T1D/T2D), surrogate imaging biomarkers for beta cell function and mass are needed. Here, we assess the potential of GPR44 as a surrogate marker for beta cells, in a direct comparison with clinically used biomarker VMAT2.

    METHODS: GPR44 surface availability was assessed by flow cytometry of human beta cells. RNA transcription levels in different pancreas compartments were evaluated. The density of GPR44 receptor in endocrine and exocrine tissues was assessed by the radiolabeled GPR44 ligand [(3)H]AZD 3825. A direct comparison with the established beta cell marker VMAT2 was performed by radiolabeled [(3)H]DTBZ.

    RESULTS: GPR44 was available on the cell surface, and pancreatic RNA levels were restricted to the islets of Langerhans. [(3)H]AZD 3825 had nanomolar affinity for GPR44 in human islets and EndoC-βH1 beta cells, and the specific binding to human beta cells was close to 50 times higher than in exocrine preparations. The endocrine-to-exocrine binding ratio was approximately 10 times higher for [(3)H]AZD 3825 than for [(3)H]DTBZ.

    CONCLUSION: GPR44 is a highly beta cell-specific target, which potentially offers improved imaging contrast between the human beta cell and the exocrine pancreas.

  • 299.
    Hellström-Lindahl, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Ericsson, Cecilia
    AstraZeneca R&D, SE-43150 Molndal, Sweden..
    O'Mahony, Gavin
    AstraZeneca R&D, SE-43150 Molndal, Sweden..
    Johnström, Peter
    Karolinska Inst, Karolinska Univ Hosp, AstraZeneca PET Sci Ctr, Personalised Healthcare & Biomarkers, SE-17176 Stockholm, Sweden..
    Skrtic, Stanko
    AstraZeneca R&D, SE-43150 Molndal, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, SE-41345 Gothenburg, Sweden..
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Toward molecular imaging of the free fatty acid receptor 12017In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 7, p. 663-668Article in journal (Refereed)
    Abstract [en]

    Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.

  • 300.
    Hering, Bernhard J.
    et al.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA.;Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Clarke, William R.
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Bridges, Nancy D.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Eggerman, Thomas L.
    NIDDK, NIH, Bethesda, MD 20892 USA..
    Alejandro, Rodolfo
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Bellin, Melena D.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA.;Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA..
    Chaloner, Kathryn
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Czarniecki, Christine W.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Goldstein, Julia S.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Hunsicker, Lawrence G.
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Kaufman, Dixon B.
    Univ Wisconsin, Dept Surg, Div Transplantat, Madison, WI USA..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsen, Christian P.
    Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA..
    Luo, Xunrong
    Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA..
    Markmann, James F.
    Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA..
    Naji, Ali
    Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA..
    Oberholzer, Jose
    Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA..
    Posselt, Andrew M.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Rickels, Michael R.
    Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA..
    Ricordi, Camillo
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Robien, Mark A.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Senior, Peter A.
    Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada.;Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada..
    Shapiro, A. M. James
    Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada.;Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada..
    Stock, Peter G.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Turgeon, Nicole A.
    Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA..
    Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia2016In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 39, no 7, p. 1230-1240Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA(1c) <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA(1c) level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

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