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  • 151.
    Dam, G.
    et al.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Grønbæk, H.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Sørbye, H.
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Thiis-Evensen, E.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Transplantat Med, Neuroendocrine Tumor Ctr Excellence, Oslo, Norway.
    Paulsson, B.
    Novartis Sverige AB, Täby, Sweden.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jensen, C.
    Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Radiol, Copenhagen, Denmark.
    Ebbesen, D.
    Aarhus Univ Hosp, Neuroendocrine Tumor Ctr Excellence, Dept Radiol, Aarhus, Denmark.
    Knigge, U.
    Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Endocrinol, Copenhagen, Denmark.;Rigshosp, Neuroendocrine Tumor Ctr Excellence, Dept Surg Gastroenterol, Copenhagen, Denmark.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    A Prospective Nordic Study on the Use of Chromogranin A for the Prediction of Progression in Patients with Pancreatic and Small Intestinal Neuroendocrine Tumors2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 152-152Article in journal (Other academic)
  • 152. Danaei, Goodarz
    et al.
    Fahimi, Saman
    Lu, Yuan
    Zhou, Bin
    Hajifathalian, Kaveh
    Di Cesare, Mariachiara
    Lo, Wei-Cheng
    Reis-Santos, Barbara
    Cowan, Melanie J.
    Shaw, Jonathan E.
    Bentham, James
    Lin, John K.
    Bixby, Honor
    Magliano, Dianna
    Bovet, Pascal
    Miranda, J. Jaime
    Khang, Young-Ho
    Stevens, Gretchen A.
    Riley, Leanne M.
    Ali, Mohammed K.
    Ezzati, Majid
    Abdeen, Ziad A.
    Kadir, Khalid Abdul
    Abu-Rmeileh, Niveen M.
    Acosta-Cazares, Benjamin
    Aekplakorn, Wichai
    Aguilar-Salinas, Carlos A.
    Ahmadvand, Alireza
    Al Nsour, Mohannad
    Alkerwi, Ala'a
    Amouyel, Philippe
    Andersen, Lars Bo
    Anderssen, Sigmund A.
    Andrade, Dolores S.
    Anjana, Ranjit Mohan
    Aounallah-Skhiri, Hajer
    Aris, Tahir
    Arlappa, Nimmathota
    Arveiler, Dominique
    Assah, Felix K.
    Avdicova, Maria
    Balakrishna, Nagalla
    Bandosz, Piotr
    Barbagallo, Carlo M.
    Barcelo, Alberto
    Batieha, Anwar M.
    Baur, Louise A.
    Ben Romdhane, Habiba
    Bernabe-Ortiz, Antonio
    Bhargava, Santosh K.
    Bi, Yufang
    Bjerregaard, Peter
    Bjorkelund, Cecilia
    Blake, Margaret
    Blokstra, Anneke
    Bo, Simona
    Boehm, Bernhard O.
    Boissonnet, Carlos P.
    Brajkovich, Imperia
    Breckenkamp, Juergen
    Brewster, Lizzy M.
    Brian, Garry R.
    Bruno, Graziella
    Bugge, Anna
    de Leon, Antonio Cabrera
    Can, Gunay
    Candido, Ana Paula C.
    Capuano, Vincenzo
    Carvalho, Maria J.
    Casanueva, Felipe F.
    Caserta, Carmelo A.
    Castetbon, Katia
    Chamukuttan, Snehalatha
    Chaturvedi, Nishi
    Chen, Chien-Jen
    Chen, Fangfang
    Chen, Shuohua
    Cheng, Ching-Yu
    Chetrit, Angela
    Chiou, Shu-Ti
    Cho, Yumi
    Chudek, Jerzy
    Cifkova, Renata
    Claessens, Frank
    Concin, Hans
    Cooper, Cyrus
    Cooper, Rachel
    Costanzo, Simona
    Cottel, Dominique
    Cowell, Chris
    Crujeiras, Ana B.
    D'Arrigo, Graziella
    Dallongeville, Jean
    Dankner, Rachel
    Dauchet, Luc
    de Gaetano, Giovanni
    De Henauw, Stefaan
    Deepa, Mohan
    Dehghan, Abbas
    Dhana, Klodian
    Di Castelnuovo, Augusto F.
    Djalalinia, Shirin
    Doua, Kouamelan
    Drygas, Wojciech
    Du, Yong
    Egbagbe, Eruke E.
    Eggertsen, Robert
    El Ati, Jalila
    Elosua, Roberto
    Erasmus, Rajiv T.
    Erem, Cihangir
    Ergor, Gul
    Eriksen, Louise
    la Penaa, Jorge Escobedo-De
    Fall, Caroline H.
    Farzadfar, Farshad
    Felix-Redondo, Francisco J.
    Ferguson, Trevor S.
    Fernandez-Berges, Daniel
    Ferrari, Marika
    Ferreccio, Catterina
    Finn, Joseph D.
    Foger, Bernhard
    Foo, Leng Huat
    Fouad, Heba M.
    Francis, Damian K.
    Franco, Maria do Carmo
    Franco, Oscar H.
    Frontera, Guillermo
    Furusawa, Takuro
    Gaciong, Zbigniew
    Galbarczyk, Andrzej
    Garnett, Sarah P.
    Gaspoz, Jean-Michel
    Gasull, Magda
    Gates, Louise
    Geleijnse, Johanna M.
    Ghasemain, Anoosheh
    Giampaoli, Simona
    Gianfagna, Francesco
    Giovannelli, Jonathan
    Gross, Marcela Gonzalez
    Rivas, Juan P. Gonzalez
    Gorbea, Mariano Bonet
    Gottrand, Frederic
    Grant, Janet F.
    Grodzicki, Tomasz
    Grontved, Anders
    Gruden, Grabriella
    Gu, Dongfeng
    Guan, Ong Peng
    Guerrero, Ramiro
    Guessous, Idris
    Guimaraes, Andre L.
    Gutierrez, Laura
    Hardy, Rebecca
    Kumar, Rachakulla Hari
    He, Jiang
    Heidemann, Christin
    Hihtaniemi, Ilpo Tapani
    Ho, Sai Yin
    Ho, Suzanne C.
    Hofman, Albert
    Russo, Andrea R. V.
    Hormiga, Claudia M.
    Horta, Bernardo L.
    Houti, Leila
    Hussieni, Abdullatif S.
    Huybrechts, Inge
    Hwalla, Nahla
    Iacoviello, Licia
    Iannone, Anna G.
    Ibrahim, Mohsen M.
    Ikeda, Nayu
    Ikram, M. Arfan
    Irazola, Vilma E.
    Islam, Muhammad
    Iwasaki, Masanori
    Jacobs, Jeremy M.
    Jafar, Tazeen
    Jasienska, Grazyna
    Jiang, Chao Qiang
    Jonas, Jost B.
    Joshi, Pradeep
    Kafatos, Anthony
    Kalter-Leibovici, Ofra
    Kasaeian, Amir
    Katz, Joanne
    Kaur, Prabhdeep
    Kavousi, Maryam
    Kelishadi, Roya
    Kengne, Andre P.
    Kersting, Mathilde
    Khader, Yousef Saleh
    Kiechl, Stefan
    Kim, Jeongseon
    Kiyohara, Yutaka
    Kolsteren, Patrick
    Korrovits, Paul
    Koskinen, Seppo
    Kratzer, Wolfgang
    Kromhout, Daan
    Kula, Krzysztof
    Kurjata, Pawel
    Kyobutungi, Catherine
    Lachat, Carl
    Laid, Youcef
    Lam, Tai Hing
    Landrove, Orlando
    Lanska, Vera
    Lappas, Georg
    Laxmaiah, Avula
    Leclercq, Catherine
    Lee, Jeannette
    Lee, Jeonghee
    Lehtimaki, Terho
    Lekhraj, Rampal
    Leon-Munoz, Luz M.
    Li, Yanping
    Lim, Wei-Yen
    Lima-Costa, M. Fernanda
    Lin, Hsien-Ho
    Lin, Xu
    Lissner, Lauren
    Lorbeer, Roberto
    Lozano, Jose Eugenio
    Lundqvist, Annamari
    Lytsy, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Ma, Guansheng
    Machado-Coelho, George L. L.
    Machi, Suka
    Maggi, Stefania
    Makdisse, Marcia
    Rao, Kodavanti Mallikharjuna
    Manios, Yannis
    Manzato, Enzo
    Margozzini, Paula
    Marques-Vidal, Pedro
    Martorell, Reynaldo
    Masoodi, Shariq R.
    Matsha, Tandi E.
    Mbanya, Jean Claude N.
    McFarlane, Shelly R.
    McGarvey, Stephen T.
    McLachlan, Stela
    McNulty, Breige A.
    Mediene-Benchekor, Sounnia
    Meirhaeghe, Aline
    Menezes, Ana Maria B.
    Merat, Shahin
    Meshram, Indrapal I.
    Mi, Jie
    Miquel, Juan Francisco
    Mohamed, Mostafa K.
    Mohammad, Kazem
    Mohan, Viswanathan
    Yusoff, Muhammad Fadhli Mohd
    Moller, Niels C.
    Molnar, Denes
    Mondo, Charles K.
    Moreno, Luis A.
    Morgan, Karen
    Moschonis, George
    Mossakowska, Malgorzata
    Mostafa, Aya
    Mota, Jorge
    Muiesan, Maria L.
    Muller-Nurasyid, Martina
    Mursu, Jaakko
    Nagel, Gabriele
    Namesna, Jana
    Nang, Ei Ei K.
    Nangia, Vinay B.
    Navarrete-Munoz, Eva Maria
    Ndiaye, Ndeye Coumba
    Nervi, Flavio
    Nguyen, Nguyen D.
    Nieto-Martinez, Ramfi S. E.
    Ning, Guang
    Ninomiya, Toshiharu
    Noale, Marianna
    Noto, Davide
    Ochoa-Aviles, Angelica M.
    Oh, Kyungwon
    Onat, Altan
    Osmond, Clive
    Otero, Johanna A.
    Palmieri, Luigi
    Panda-Jonas, Songhomitra
    Panza, Francesco
    Parsaeian, Mahboubeh
    Peixoto, Sergio Viana
    Pereira, Alexandre C.
    Peters, Annette
    Peykari, Niloofar
    Pilav, Aida
    Pitakaka, Freda
    Piwonska, Aleksandra
    Piwonski, Jerzy
    Plans-Rubio, Pedro
    Porta, Miquel
    Portegies, Marileen L. P.
    Poustchi, Hossein
    Pradeepa, Rajendra
    Price, Jacqueline F.
    Punab, Margus
    Qasrawi, Radwan F.
    Qorbani, Mostafa
    Raitakari, Olli
    Rao, Sudha Ramachandra
    Ramachandran, Ambady
    Ramos, Rafel
    Rampal, Sanjay
    Rathmann, Wolfgang
    Redon, Josep
    Reganit, Paul Ferdinand M.
    Rigo, Fernando
    Robinson, Sian M.
    Robitaille, Cynthia
    Rodriguez, Laura A.
    Rodriguez-Artalejo, Fernando
    Rodriguez-Perez, Maria del Cristo
    Rojas-Martinez, Rosalba
    Romaguera, Dora
    Rosengren, Annika
    Rubinstein, Adolfo
    Rui, Ornelas
    Ruiz-Betancourt, Blanca Sandra
    Rutkowski, Marcin
    Sabanayagam, Charumathi
    Sachdev, Harshpal S.
    Saidi, Olfa
    Sakarya, Sibel
    Salanave, Benoit
    Salonen, Jukka T.
    Salvetti, Massimo
    Sanchez-Abanto, Jose
    Nunes, Renata
    Santos, Rute
    Sardinha, Luis B.
    Scazufca, Marcia
    Schargrodsky, Herman
    Scheidt-Nave, Christa
    Shibuya, Kenji
    Shin, Youchan
    Shiri, Rahman
    Siantar, Rosalynn
    Sibai, Abla M.
    Simon, Mary
    Simons, Judith
    Simons, Leon A.
    Sjostrom, Michael
    Slowikowska-Hilczer, Jolanta
    Slusarczyk, Przemyslaw
    Smeeth, Liam
    Snijder, Marieke B.
    Solfrizzi, Vincenzo
    Sonestedt, Emily
    Soumare, Aicha
    Staessen, Jan A.
    Steene-Johannessen, Jostein
    Stehle, Peter
    Stein, Aryeh D.
    Stessman, Jochanan
    Stockl, Doris
    Stokwiszewski, Jakub
    Strufaldi, Maria Wany
    Sun, Chien-An
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Suriyawongpaisal, Paibul
    Sy, Rody G.
    Tai, E. Shyong
    Tarawneh, Mohammed
    Tarqui-Mamani, Carolina B.
    Thijs, Lutgarde
    Tolstrup, Janne S.
    Topbas, Murat
    Torrent, Maties
    Traissac, Pierre
    Trinh, Oanh T. H.
    Tulloch-Reid, Marshall K.
    Tuomainen, Tomi-Pekka
    Turley, Maria L.
    Tzourio, Christophe
    Ueda, Peter
    Ukoli, Flora M.
    Ulmer, Hanno
    Valdivia, Gonzalo
    Van Valkengoed, Irene G. M.
    Vanderschueren, Dirk
    Vanuzzo, Diego
    Vega, Tomas
    Velasquez-Melendez, Gustavo
    Veronesi, Giovanni
    Verschuren, Monique
    Vioque, Jesus
    Virtanen, Jyrki
    Visvikis-Siest, Sophie
    Viswanathan, Bharathi
    Vollenweider, Peter
    Voutilainen, Sari
    Wade, Alisha N.
    Wagner, Aline
    Walton, Janette
    Mohamud, Wan Nazaimoon Wan
    Wang, Ming-Dong
    Wang, Ya Xing
    Wannamethee, S. Goya
    Weerasekera, Deepa
    Whincup, Peter H.
    Widhalm, Kurt
    Wiecek, Andrzej
    Wilks, Rainford J.
    Willeit, Johann
    Wojtyniak, Bogdan
    Wong, Tien Yin
    Woo, Jean
    Woodward, Mark
    Wu, Aleksander Giwercman
    Wu, Frederick C.
    Wu, Shou Ling
    Xu, Haiquan
    Yang, Xiaoguang
    Ye, Xingwang
    Yoshihara, Akihiro
    Younger-Coleman, Novie O.
    Zambon, Sabina
    Zargar, Abdul Hamid
    Zdrojewski, Tomasz
    Zhao, Wenhua
    Zheng, Yingfeng
    Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331288 participants2015In: LANCET DIABETES & ENDOCRINOLOGY, ISSN 2213-8587, Vol. 3, no 8, p. 624-637Article in journal (Refereed)
    Abstract [en]

    Background Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA(1c). We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA(1c) (HbA(1c) >= 6 . 5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG >= 7 . 0 mmol/L or 2hOGTT >= 11 . 1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG- or-2hOGTT was correlated with prevalence based on FPG alone (r= 0 . 98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA(1c) was lower than prevalence based on FPG in 42 . 8% of age-sex-survey groups and higher in another 41 . 6%; in the other 15 . 6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA(1c)-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA(1c) 6 . 5% or more had a pooled sensitivity of 52 . 8% (95% CI 51 . 3-54 . 3%) and a pooled specificity of 99 . 74% (99 . 71-99 . 78%) compared with FPG 7 . 0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30 . 5% (28 . 7-32 . 3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA(1c) versus FPG. Interpretation Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA(1c)-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test.

  • 153.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. 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.
    Drobin, Kimi
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    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.
    Nilsson, Peter
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Schwenk, Jochen M.
    KTH - Royal Institute of Technology, Stockholm, Sweden.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e81712-Article in journal (Refereed)
    Abstract [en]

    Background

    Patients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.

    Materials and methods

    Suspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.

    Results

    A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.

    Conclusions

    We propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.

  • 154.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Chatzelis, Eleftherios
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece;251 Hellen Air Force & VA Gen Hosp, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Papadopoulou-Marketou, Nektaria
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Linkoping, Sweden.
    Dimitriadis, Georgios K.
    Univ Hosp Coventry & Warwickshire NHS Trust, Arden Net CoE & Human Metab Res Unit HMRU, WISDEM, Coventry CV2 2DX, W Midlands, England.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology. Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Univ Hosp Solna, CCK, R8 04, Stockholm, Sweden.
    Kaltsas, Gregory
    Univ Athens, Laiko Hosp, Dept Propauped Internal Med 1, Oncol Unit, Athens, Greece.
    Endocrine paraneoplastic syndromes in patients with neuroendocrine neoplasms2019In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 64, no 2, p. 384-392Article in journal (Refereed)
    Abstract [en]

    Objective: Our aim was to assess the prevalence of endocrine paraneoplastic syndromes (EPNS) in neuroendocrine neoplasms (NENs) and estimate its impact on patient outcomes.

    Design: This is a retrospective analysis of 834 patients with NENs (611 gastrointestinal, 166 thoracic, 57 of unknown and various other primary origin). We included 719 consecutive NEN patients treated at EKPA-Laiko Hospital, Athens, Greece and 115 patients with lung carcinoid (LC) treated at Uppsala University Hospital, Uppsala, Sweden. EPNS diagnosis was based on standard criteria.

    Methods: Twenty-one patients with EPNS were detected: 16 with ectopic Cushing's syndrome (ECS), one with hypercalcaemia due to parathyroid hormone-related protein (PTHrP) secretion, three with hypercalcitonaemia and one patient with dual secretion of calcitonin and beta-human chorionic gonadotropin (-HCG). All tumours were well-differentiated; 10 patients had Stage IV disease at diagnosis.

    Results: The prevalence of EPNS in the Greek cohort was 1.9%, whereas that of ECS among LC patients in both centres was 6.7%. Median overall survival (OS) for patients with EPNS was 160.7 months (95%CI, 86-235.4) and median event-free survival (EFS) was 25.9 months (95%CI, 0-57.2). Patients presenting with EPNS prior to NEN diagnosis had longer EFS compared to patients with synchronous or metachronous EPNS (log-rank P=0.013). Patients with ECS of extra-thoracic origin demonstrated shorter OS and EFS compared to patients with ECS of lung or thymic origin (log-rank P=0.001 and P<0.001, respectively). LC patients with and without ECS were comparable in 5-year and 10-year OS rates (66.7% and 33.3% versus 89.8% and 60.2%, respectively; 95%CI [189.6-300.4 months], log-rank P=0.94) and in median EFS, 67 versus 183 months, 95%CI [50.5-207.5], log-rank P=0.12).

    Conclusion: EPNS are relatively rare in patients with NENs and mainly concern well-differentiated tumours of the foregut. Among patients with EPNS, LC-related ECS may not adversely affect patient outcomes when diagnosed prior to NEN and effectively been treated.

  • 155.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Edfeldt, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Midkine Is a New Novel Serum Biomarker in Small Intestinal Neuroendocrine Tumors (SI-NETs)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 45-45Article in journal (Refereed)
  • 156.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karakatsanis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ex Vivo Activity of Cytotoxic Drugs and Targeted Agents in Small Intestinal Neuroendocrine Tumors2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 189-189Article in journal (Other academic)
  • 157.
    Daskalakis, Kosmas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Tsoli, Marina
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Srirajaskanthan, Raj
    Kings Coll Hosp London, Neuroendocrine Tumour Unit, Kings Coll Hosp, KHP ENETS Ctr Excellence,Dept Gastroenterol, London SE5 9RS, England.
    Chatzellis, Eleftherios
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Alexandraki, Krystallenia
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Angelousi, Anna
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece.
    Pizanias, Michail
    Kings Coll Hosp London, Dept Liver Transplantat, Inst Liver Studies,Hepatobiliary Pancreat Surg, Kings Healthcare Partners,NHS FT, Denmark Hill, London, England.
    Randeva, Harpal
    Univ Warwick, Warwick Med Sch, Clin Sci Res Labs, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    Kaltsas, Gregory
    Univ Athens, Dept Propauped Internal Med 1, Endocrine Oncol Unit, Laiko Hosp, Athens, Greece;Univ Warwick, Warwick Med Sch, Clin Sci Res Labs, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    Weickert, Martin O.
    Univ Hosp Coventry & Warwickshire NHS Trust, ARDEN NET Ctr, European Neuroendocrine Tumour Soc ENETS, Ctr Excellence CoE, Coventry, W Midlands, England;Univ Warwick, Warwick Med Sch, Clin Sci Res Labs, Univ Hosp, Coventry, W Midlands, England;Coventry Univ, Ctr Appl Biol & Exercise Sci, Fac Hlth & Life Sci, Coventry, W Midlands, England.
    Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no 4, p. 308-316Article in journal (Refereed)
    Abstract [en]

    Background/Aims: To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. Methods: Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. Results: LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1-150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6-71.6] vs. 122.7 [95% CI 70.7-174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07-0.45; p< 0.0001). Conclusion: LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients' outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.

  • 158.
    De Felice, Fernanda G.
    et al.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo Meis, Rio De Janeiro, Brazil.;DOr Inst Res & Educ, Rio De Janeiro, Brazil.;Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A Key Role of Insulin Receptors in Memory2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 11, p. 3653-3655Article in journal (Other academic)
  • 159.
    Decker, Ralph
    et al.
    Univ Gothenburg, Gothenburg Pediat Growth Res Ctr, Dept Pediat, Inst Clin Sci,Sahlgrenska Acad, S-41685 Gothenburg, Sweden;MVZ Praxis Chilehaus Pediat Endocrinol Androl Int, D-20095 Hamburg, Germany.
    Albertsson-Wikland, Kerstin
    Univ Gothenburg, Dept Physiol Endocrinol, Inst Neurosci & Physiol, Sahlgrenska Acad, S-41685 Gothenburg, Sweden.
    Kriström, Berit
    Umea Univ, Dept Pediat, Inst Clin Sci, S-90187 Umea, Sweden.
    Halldin, Maria
    Karolinska Inst, Dept Womens & Childrens Hlth, Div Pediat Endocrinol, S-17177 Stockholm, Sweden.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology.
    Nilsson, Nils-Östen
    Halland Hosp, Dept Pediat, S-30233 Halmstad, Sweden.
    Dahlgren, Jovanna
    Univ Gothenburg, Gothenburg Pediat Growth Res Ctr, Dept Pediat, Inst Clin Sci,Sahlgrenska Acad, S-41685 Gothenburg, Sweden.
    GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children2019In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 3, p. 835-844Article in journal (Refereed)
    Abstract [en]

    Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period.

    Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period.

    Design and Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non-GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 μg/kg/d (GHFIX)].

    Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUID and GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose.

    Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was -0.75 ± 1.0 at 3 months (P = 0.003) and -0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02).

    Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ± 2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

  • 160.
    Delle Fave, G.
    et al.
    Osped St Andrea, Dept Digest & Liver Dis, Rome, Italy.;Univ Roma La Sapienza, Dept Digest & Liver Dis, Via Grottarossa 1035, IT-00189 Rome, Italy..
    O'Toole, D.
    St Vincents Univ, NET Ctr, Dublin, Ireland.;St James Hosp, Dept Clin Med, Dublin 8, Ireland.;Univ Dublin Trinity Coll, Dublin 2, Ireland..
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Taal, B.
    Netherlands Canc Ctr, Lijnden, Netherlands..
    Ferolla, P.
    Univ Perugia, Umbria Reg Canc Network, NET Ctr, I-06100 Perugia, Italy..
    Ramage, J. K.
    Hampshire Hosp NHS Trust, Dept Gastroenterol, Winchester, Hants, England..
    Ferone, D.
    Univ Genoa, Dept Endocrine & Metab Sci, Genoa, Italy..
    Ito, T.
    Kyushu Univ Hosp, Pancreat Dis Branch, Fukuoka 812, Japan..
    Weber, W.
    Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Zheng-Pei, Z.
    Beijing Union Med Coll Hosp, Dept Endocrinol, Beijing, Peoples R China..
    De Herder, W. W.
    Erasmus MC, Div Endocrinol, Dept Internal Med, Rotterdam, Netherlands..
    Pascher, A.
    Charite, Dept Visceral & Transplant Surg, Campus Virchow Klinikum, D-13353 Berlin, Germany..
    Ruszniewski, P.
    Beaujon Hosp, Dept Gastroenterol, Clichy, France..
    ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, no 2, p. 119-124Article in journal (Refereed)
  • 161. Denison, H
    et al.
    Nilsson, C
    Löfgren, L
    Himmelmann, A
    Mårtensson, G
    Knutsson, M
    Al-Shurbaji, A
    Tornqvist, H
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial2014In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, no 4, p. 334-343Article in journal (Refereed)
    Abstract [en]

    AIM:

    Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.

    METHODS:

    Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.

    RESULTS:

    Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.

    CONCLUSIONS:

    Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

  • 162.
    Derraik, Jose G. B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand.
    Miles, Harriet L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Chiavaroli, Valentina
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, Better Start Natl Sci Challenge, Auckland, New Zealand.
    Idiopathic short stature and growth hormone sensitivity in prepubertal children2019In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 91, no 1, p. 110-117Article in journal (Refereed)
    Abstract [en]

    Objective: We compared growth hormone sensitivity to an insulin-like growth factor I (IGF-I) generation test in children with idiopathic short stature (ISS) and of normal stature (NS) across the birthweight range.

    Methods: Forty-six prepubertal children (~7.1 years) born at term were studied: ISS (n = 23; 74% boys) and NS (n = 23; 57% boys). Children underwent a modified IGF-I generation test with recombinant human growth hormone (rhGH; 0.05 mg/kg/d) over four consecutive days. Hormonal concentrations were measured at baseline and day 5.

    Results: Children with idiopathic short stature were 1.90 SDS lighter (P < 0.0001) but had 4.5% more body fat (P = 0.0007) than NS children. Overall, decreasing birthweight SDS across the normal range (-1.9 to +1.5 SDS) was associated with lower percentage IGF-I response to rhGH stimulation in univariable (r = 0.45; P = 0.002) and multivariable models (β = 24.6; P = 0.006). Plasma IGF-I concentrations rose in both groups with rhGH stimulation (P < 0.0001). GHBP levels (P = 0.002) were suppressed in ISS children (-19%; P = 0.029) but increased among NS children (+18%; P = 0.028), with contrasting responses also observed for leptin and IGFBP-1. Further, the increase in insulin concentrations in response to rhGH stimulation was ~3-fold greater in NS children (142% vs 50%; P = 0.006).

    Conclusions: A progressive decrease in birthweight SDS was associated with a reduction in GH sensitivity in both NS and ISS children. Thus, the lower IGF-I response to rhGH stimulation in association with decreasing birthweight indicates that the ISS children at the lower end of the birthweight spectrum may have partial GH resistance, which may contribute to their poorer growth.

  • 163.
    Diakatou, Evanthia
    et al.
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Alexandraki, Krystallenia I.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Kontogeorgos, George
    G Gennimatas Athens Gen Hosp, Dept Pathol, Athens, Greece..
    Chatzellis, Eleftherios
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Leonti, Anastasia
    Alexandra Hosp, Dept Nucl Med, Athens, Greece..
    Kaltsas, Gregory A.
    Univ Athens, Dept Pathophysiol, Athens, Greece..
    Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 3, p. 420-428Article in journal (Refereed)
    Abstract [en]

    ContextThe expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. ObjectiveTo investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. DesignProspective two-centre study. Patients and measurementsWe analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n=54) and metastatic (n=27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. ResultsSstr2 was the commonest sstr expressed (654%) and was co-expressed with sstr3 and sstr5 in 321% and 247% of the specimens, respectively. In 67 of 81 specimens (827%), there was concordance of sstr2 immunohistochemistry with SRS findings (P<0001). D2R was expressed in only 8 of 23 (348%) GI-NENs while was co-expressed with sstr2 in all cases. SRS grade, as per Krenning scale, was higher in metastatic foci, large-size (>2cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r=06, P<0001) and D2R (r=05, P<0001) IHC intensity scores than tumour size (r=04, P<0001) and sstr3 (r=04, P<0001) intensity score. ConclusionsSstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours.

  • 164.
    Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavalli, Marco
    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.
    Pan, Gang
    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.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kumar, Chanchal
    AstraZeneca, R&D BioPharmaceut, Translat Sci & Expt Med, Early Cardiovasc Renal & Metab, Gothenburg, Sweden;Karolinska Inst, AstraZeneca Integrated CardioMetab Ctr KI AZ ICMC, Dept Med, Huddinge, Sweden.
    Skrtic, Stanko
    AstraZeneca AB, Pharmaceut Technol & Dev, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9653Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.

  • 165.
    Diderholm, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Beardsall, Kathryn
    Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Murgatroyd, Peter
    Addenbrookes Hosp, Wellcome Trust Clin Res Facil, Cambridge, England..
    Lees, Christoph
    Rosie Matern Hosp, Dept Obstet & Gynaecol, Cambridge, England..
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dunger, David
    Univ Cambridge, Addenbrookes Hosp NHS Fdn Trust, Dept Paediat, Cambridge, England..
    Maternal rates of lipolysis and glucose production in late pregnancy are independently related to foetal weight2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 87, no 3, p. 272-278Article in journal (Refereed)
    Abstract [en]

    Objective: Associations between maternal glucose levels and increased foetal growth are well established, and independent relationships with maternal weight, weight gain and insulin resistance are also observed. The relative roles of lipolysis and glucose production in the determination of these observations remain unclear. Design: We examined, through detailed physiological studies, the relationship between maternal late gestational energy substrate production (glucose and glycerol), maternal weight and weight gain, and estimated foetal size in the third trimester. Patients: Twenty-one nulliparous pregnant women, without gestational diabetes (GDM) assessed at 28 weeks with oral glucose tolerance test, were recruited. Measurements: Rates of hepatic glucose production (GPR) and rates of glycerol production (reflecting lipolysis) using [C-13(6)]-glucose and [H-2(5)]-glycerol were measured at 34-36 weeks of gestation. Respiratory quotient was assessed by indirect calorimetry and body composition by measurements of total body water (TBW; (H2O)-O-18) and body density (BODPOD). Foetal weight was estimated from ultrasound measures of biparietal diameter, femoral length and abdominal circumference. Results: At 34-36 weeks, bivariate analyses showed that GPR and lipolysis correlated with estimated foetal weight (r=.71 and .72, respectively) as well as with maternal weight, fat mass and fat-free mass, but not maternal weight gain. In multivariate analyses, rates of both glucose production (r=.42) and lipolysis (r=.47) were independently associated with foetal size explaining 63% of the variance. Conclusions: Both maternal rates of lipolysis and hepatic glucose production in late gestation are strongly related to estimated foetal weight.

  • 166.
    Dillon, J.
    et al.
    Univ Iowa, Iowa City, IA USA.
    Kulke, M.
    Dana Farber Canc Inst, Boston, MA USA.
    Warner, R.
    Icahn Sch Med Mt Sinai, New York, NY USA.
    Bergsland, E.
    Univ Calif San Francisco, San Francisco, CA USA.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    O'Dorisio, T.
    Univ Iowa, Iowa City, IA USA.
    Mckee, C.
    Lexicon Pharmaceut, The Woodlands, TX USA.
    Lapuerta, P.
    Lexicon Pharmaceut, The Woodlands, TX USA.
    Pavel, M.
    Friedrich Alexander Univ, Erlangen, Germany.
    Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Two Phase 3 Studies in Carcinoid Syndrome2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 224-224Article in journal (Other academic)
  • 167. Dimas, Antigone S.
    et al.
    Lagou, Vasiliki
    Barker, Adam
    Knowles, Joshua W.
    Maegi, Reedik
    Hivert, Marie-France
    Benazzo, Andrea
    Rybin, Denis
    Jackson, Anne U.
    Stringham, Heather M.
    Song, Ci
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Fischer-Rosinsky, Antje
    Boesgaard, Trine Wellov
    Grarup, Niels
    Abbasi, Fahim A.
    Assimes, Themistocles L.
    Hao, Ke
    Yang, Xia
    Lecoeur, Cecile
    Barroso, Ines
    Bonnycastle, Lori L.
    Boettcher, Yvonne
    Bumpstead, Suzannah
    Chines, Peter S.
    Erdos, Michael R.
    Graessler, Jurgen
    Kovacs, Peter
    Morken, Mario A.
    Narisu, Narisu
    Payne, Felicity
    Stancakova, Alena
    Swift, Amy J.
    Toenjes, Anke
    Bornstein, Stefan R.
    Cauchi, Stephane
    Froguel, Philippe
    Meyre, David
    Schwarz, Peter E. H.
    Haering, Hans-Ulrich
    Smith, Ulf
    Boehnke, Michael
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Tuomilehto, Jaakko
    Quertemous, Thomas
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hansen, Torben
    Pedersen, Oluf
    Walker, Mark
    Pfeiffer, Andreas F. H.
    Spranger, Joachim
    Stumvoll, Michael
    Meigs, James B.
    Wareham, Nicholas J.
    Kuusisto, Johanna
    Laakso, Markku
    Langenberg, Claudia
    Dupuis, Josee
    Watanabe, Richard M.
    Florez, Jose C.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    McCarthy, Mark I.
    Prokopenko, Inga
    Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 6, p. 2158-2171Article in journal (Refereed)
    Abstract [en]

    Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

  • 168.
    Doroszko, Milena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Turku, Inst Biomed, Turku, Finland.
    Chrusciel, Marcin
    Univ Turku, Inst Biomed, Turku, Finland.
    Stelmaszewska, Joanna
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Slezak, Tomasz
    Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
    Anisimowicz, Slawomir
    Ctr Gynecol & Reprod Endocrinol Artemida, Bialystok, Poland.
    Plöckinger, Ursula
    Charite Univ Med Berlin, Interdisciplinary Ctr Metab Endocrinol Diabet & M, Berlin, Germany.
    Quinkler, Marcus
    Endocrinol Charlottenburg, Berlin, Germany;Charite Univ Med Berlin, Charite Campus Mitte, Dept Clin Endocrinol, Berlin, Germany.
    Bonomi, Marco
    Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy.
    Wolczynski, Slawomir
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Huhtaniemi, Ilpo
    Univ Turku, Inst Biomed, Turku, Finland;Imperial Coll London, Fac Med, Dept Surg & Canc, London, England.
    Toppari, Jorma
    Univ Turku, Inst Biomed, Turku, Finland;Turku Univ Hosp, Dept Pediat, Turku, Finland.
    Rahman, Nafis A.
    Univ Turku, Inst Biomed, Turku, Finland;Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    GnRH antagonist treatment of malignant adrenocortical tumors2019In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 1, p. 103-117Article in journal (Refereed)
    Abstract [en]

    Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse C alpha 1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin a promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

  • 169.
    Drott, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Franzén, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    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.
    Ghrelin in rat pancreatic islets decreases islet blood flow2019In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 317, no 1, p. E139-E146Article in journal (Refereed)
    Abstract [en]

    The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the epsilon-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1 alpha). exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1 alpha receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1 alpha was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats. only, also improved the peak insulin response to glucose in vivo. thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.

  • 170.
    Drott, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Franzén, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ghrelin in rat pancreatic islets decreases islet blood flow and impairs insulin secretion2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S218-S218Article in journal (Other academic)
  • 171.
    Drzazga, Anna
    et al.
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Salaga, Maciej
    Med Univ Lodz, Dept Biochem, Mazowiecka 6-8, PL-92215 Lodz, Poland.
    Zatorski, Hubert
    Med Univ Lodz, Dept Biochem, Mazowiecka 6-8, PL-92215 Lodz, Poland.
    Koziolkiewicz, Maria
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Gendaszewska-Darmach, Edyta
    Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, B Stefanowskiego 4-10, PL-90924 Lodz, Poland.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lysophosphatidylcholine and its phosphorothioate analogues potentiate insulin secretion via GPR40 (FFAR1), GPR55 and GPR119 receptors in a different manner2018In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 472, p. 117-125Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidylcholine (LPC) is an endogenous ligand for GPR119 receptor, mediating glucose-stimulated insulin secretion (GSIS). We demonstrate that LPC facilitates GSIS in MINE pancreatic beta-cell line and murine islets of Langerhans by recognizing not only GPR119 but also GPR40 (free fatty acid receptor 1) and GPR55 activated by lysophosphatidylinositol. Natural LPCs are unstable when administered in vivo limiting their therapeutic value and therefore, we present phosphorothioate LPC analogues with increased stability. All the modified LPCs under study (12:0,14:0,16:0,18:0, and 18:1) significantly enhanced GSIS. The 16:0 sulfur analogue was the most potent, evoking 2-fold accentuated GSIS compared to the native counterpart. Interestingly, LPC analogues evoked GPR40-, GPR55-and GPR119 dependent [Ca2+](i), signaling, but did not stimulate cAMP accumulation as in the case of unmodified molecules. Thus, introduction of a phosphorothioate function not only increases LPC stability but also modulates affinity towards receptor targets and evokes different signaling pathways.

  • 172.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Kharaziha, Pedram
    Chioureas, Dimitris
    Meersman, Niels
    Panaretakis, Theocharis
    Ronquist, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Malignant Cell-Derived Extracellular Vesicles Express Different Chromogranin Epitopes Compared to Prostasomes2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 10, p. 1063-1073Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS. We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS. A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION. Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers.

  • 173.
    Dyachok, Oleg
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+-induced Ca2+ Release via Inositol 1,4,5-trisphosphate Receptors Is Amplified by Protein Kinase A and Triggers Exocytosis in Pancreatic β-Cells2004In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, no 44, p. 45455-45461Article in journal (Refereed)
    Abstract [en]

    Hormones, such as glucagon and glucagon-like peptide-1, potently amplify nutrient stimulated insulin secretion by raising cAMP. We have studied how cAMP affects Ca2+-induced Ca2+ release (CICR) in pancreatic β-cells from mice and rats and the role of CICR in secretion. CICR was observed as pronounced Ca2+ spikes on top of glucose- or depolarization-dependent rise of the cytoplasmic Ca2+ concentration ([Ca2+]i). cAMP-elevating agents strongly promoted CICR. This effect involved sensitization of the receptors underlying CICR, because many cells exhibited the characteristic Ca2+ spiking at low or even in the absence of depolarization-dependent elevation of [Ca2+]i. The cAMP effect was mimicked by a specific activator of protein kinase A in cells unresponsive to activators of cAMP-regulated guanine nucleotide exchange factor. Ryanodine pretreatment, which abolishes CICR mediated by ryanodine receptors, did not prevent CICR. Moreover, a high concentration of caffeine, known to activate ryanodine receptors independently of Ca2+, failed to mobilize intracellular Ca2+. On the contrary, a high caffeine concentration abolished CICR by interfering with inositol 1,4,5-trisphosphate receptors (IP3Rs). Therefore, the cell-permeable IP3R antagonist 2-aminoethoxydiphenyl borate blocked the cAMP-promoted CICR. Individual CICR events in pancreatic β-cells were followed by [Ca2+]i spikes in neighboring human erythroleukemia cells, used to report secretory events in the β-cells. The results indicate that protein kinase A-mediated promotion of CICR via IP3Rs is part of the mechanism by which cAMP amplifies insulin release.

  • 174.
    Dyachok, Oleg
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Tufveson, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Gylfe, Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+-induced Ca2+ release by activation of inositol 1,4,5-trisphosphate receptors in primary pancreatic β-cells2004In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 36, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The effect of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) inhibition on the cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in primary insulin-releasing pancreatic β-cells isolated from mice, rats and human subjects as well as in clonal rat insulinoma INS-1 cells. In Ca2+-deficient medium the individual primary β-cells reacted to the SERCA inhibitor cyclopiazonic acid (CPA) with a slow rise of [Ca2+]i followed by an explosive transient elevation. The [Ca2+]i transients were preferentially observed at low intracellular concentrations of the Ca2+ indicator fura-2 and were unaffected by pre-treatment with 100 μM ryanodine. Whereas 20 mM caffeine had no effect on basal [Ca2+]i or the slow rise in response to CPA, it completely prevented the CPA-induced [Ca2+]i transients as well as inositol 1,4,5-trisphosphate-mediated [Ca2+]i transients in response to carbachol. In striking contrast to the primary β-cells, caffeine readily mobilized intracellular Ca2+ in INS-1 cells under identical conditions, and such mobilization was prevented by ryanodine pre-treatment. The results indicate that leakage of Ca2+ from the endoplasmic reticulum after SERCA inhibition is feedback-accelerated by Ca2+-induced Ca2+ release (CICR). In primary pancreatic β-cells this CICR is due to activation of inositol 1,4,5-trisphosphate receptors. CICR by ryanodine receptor activation may be restricted to clonal β-cells.

  • 175.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ahmad, Tanveer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Janson, Eva T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    TCEB3C a putative tumor suppressor gene of small intestine neuroendocrine tumors2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 2, p. 275-284Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs), formerly midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, Western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. The large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one TCEB3C gene copy. The DNA hypomethylating agent 5-aza-2'-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease of clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.

  • 176.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Daskalakis, Kosmas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 2, p. 170-181Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.

  • 177.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stalberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    ACTG2 Inhibits Growth and Is Epigenetically Repressed in Small Intestinal Neuroendocrine Tumors2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 227-227Article in journal (Other academic)
  • 178.
    Edfeldt, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    A plausible role for actin gamma smooth muscle 2 (ACTG2) in small intestinal neuroendocrine tumorigenesis2016In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 16, no 19Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from the enterochromaffin cells in the ileum and jejunum. The knowledge about genetic and epigenetic abnormalities is limited. Low mRNA expression levels of actin gamma smooth muscle 2 (ACTG2) have been demonstrated in metastases relative to primary SI-NETs. ACTG2 and microRNA-145 (miR-145) are aberrantly expressed in other cancers and ACTG2 can be induced by miR-145. The aim of this study was to investigate the role of ACTG2 in small intestinal neuroendocrine tumorigenesis.

    METHODS: Protein expression was analyzed in SI-NETs (n = 24) and in enterochromaffin cells by immunohistochemistry. The cell line CNDT2.5 was treated with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep), the selective EZH2 inhibitor EPZ-6438, or 5-aza-2'-deoxycytidine, a DNA hypomethylating agent. Cells were transfected with ACTG2 expression plasmid or miR-145. Western blotting analysis, quantitative RT-PCR, colony formation- and viability assays were performed. miR-145 expression levels were measured in tumors.

    RESULTS: Eight primary tumors and two lymph node metastases displayed variable levels of positive staining. Fourteen SI-NETs and normal enterochromaffin cells stained negatively. Overexpression of ACTG2 significantly inhibited CNDT2.5 cell growth. Treatment with DZNep or transfection with miR-145 induced ACTG2 expression (>10-fold), but no effects were detected after treatment with EPZ-6438 or 5-aza-2'-deoxycytidine. DZNep also induced miR-145 expression. SI-NETs expressed relatively low levels of miR-145, with reduced expression in metastases compared to primary tumors.

    CONCLUSIONS: ACTG2 is expressed in a fraction of SI-NETs, can inhibit cell growth in vitro, and is positively regulated by miR-145. Theoretical therapeutic strategies based on these results are discussed.

  • 179.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Frisk, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Trace Element Changes in Thoracic Aortic Dissection2016In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 169, no 2, p. 159-163Article in journal (Refereed)
    Abstract [en]

    Thoracic aortic dissection is a life-threatening condition with an incompletely understood pathogenesis. Trace elements are essential for the functioning of different processes in the body, including the immune system and associated responses to infection/inflammation. Because inflammation may be part of the pathogenesis of thoracic aortic dissection, we investigated whether trace element changes associated with inflammation occur in serum and tissue samples during the disease. The study included 21 patients undergoing surgery for thoracic aortic dissection, 10 forensic autopsy specimens for tissue controls and 23 healthy blood donors for serum controls. Levels of magnesium (Mg), calcium (Ca), vanadium (V), manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd) and mercury (Hg) were measured in the aortic tissue and serum by inductively coupled plasma-mass spectrometry (ICP-MS). In the serum, Ca, V, Cu and Zn decreased, whereas Fe increased. In the tissue, Cu and Zn decreased and Fe tended to increase. The Cu/Zn ratio in the serum, a marker of infection/inflammation, did not change in the patients. Concerning trace element changes in the serum and tissue, our data do not support the hypothesis that inflammation is involved in the pathogenesis of thoracic aortic dissection.

  • 180.
    Edén, Desireé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mokhtari, Dariush
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, p. 2563-2572Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Patients diagnosed with type 1 or type 2 diabetes have elevated levels of coagulation factor VIIa (FVIIa) and its receptor tissue factor (TF) in their bloodstream. This may affect the fate of the beta cells. We aimed to study the effects of TF/FVIIa signalling on cytokine-induced beta cell death and islet function in vitro. Methods Human pancreatic islets and MIN-6 beta cells were used to study TF mRNA and protein expression using real-time PCR, immunoblotting and flow cytometry. The effects of TF/FVIIa on cytokine-induced beta cell death were studied in MIN-6 cells and human pancreatic islets using cell-death ELISA and propidium iodide and cleaved caspase-3 staining. Effects of TF/FVIIa on the phosphorylation of p38, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) were investigated by immunoblotting. Glucose-stimulated insulin secretion (GSIS) from human islets was measured with an insulin ELISA. Results A combination of the cytokines IL-1 beta, TNF-alpha and IFN-gamma induced TF expression in human pancreatic islets and in beta cells. TF/FVIIa did not affect basal beta cell death but, independently of downstream coagulation activity, augmented beta cell death in response to cytokines. The effect of TF/FVIIa on cytokine-induced beta cell death was found to be dependent on the stress kinase JNK, since FVIIa addition potentiated cytokine-induced JNK activation and JNK inhibition abolished the effect of TF/FVIIa on cytokine-induced beta cell death. Moreover, TF/FVIIa signalling resulted in inhibition of GSIS from human pancreatic islets. Conclusions/interpretation These results indicate that TF/FVIIa signalling has a negative effect on beta cell function and promotes beta cell death in response to cytokines.

  • 181. Eeg-Olofsson, K
    et al.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Nilsson, P M
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Svensson, A-M
    Gudbjörnsdóttir, S
    Eliasson, B
    New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR).2010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 268, no 5, p. 471-482Article in journal (Refereed)
    Abstract [en]

    AIMS

    To analyse the association between glycosylated haemoglobin A1c (HbA1c) and cardiovascular disease (CVD) in patients with type 2 diabetes in the Swedish National Diabetes Register (NDR).

    METHODS

    An observational study of 18 334 patients (age 30-79 years, previous CVD in 18%, baseline HbA1c 5.0-10.9%) who were followed for 6 years (mean 5.6 years) from 1997/1998 until 2003.

    RESULTS

    Hazard ratios per 1% unit increase in baseline or updated mean HbA1c for fatal/nonfatal coronary heart disease (CHD), CVD and total mortality were 1.11-1.13, 1.10-1.11 and 1.09-1.10, respectively (all P < 0.001), adjusted for several risk factors and clinical characteristics in Cox regression. Adjusted 6-year event rates increased with higher baseline or updated mean HbA1c with no J-shaped risk curves, in all patients and also when subgrouping by shorter (mean 3 years) or longer (mean 14 years) diabetes duration, by presence or absence of previous CVD, or by treatment with oral hypoglycaemic agents (OHAs) or insulin. Risk reductions of 20% for CHD and 16% for CVD (P < 0.001) were found in patients with a baseline mean HbA1c of 6.5%, compared to those with a mean level of 7.5%. Compared to OHA-treated patients, insulin-treated patients had an increased risk of total mortality, due almost exclusively to an increased risk of non-CVD mortality, and due less to a weakly significant increased risk of fatal CVD. HbA1c was not associated with non-CVD mortality.

    CONCLUSIONS

    This observational study showed progressively increasing risks of CHD, CVD and total mortality with higher HbA1c, and no risk increase at low HbA1c levels even with longer diabetes duration, previous CVD or treatment with either insulin or OHAs. Patients achieving HbA1c <7% showed benefits for risk reduction.

  • 182. Eeg-Olofsson, K.
    et al.
    Gudbjornsdottir, S.
    Eliasson, B.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Svensson, A. -M
    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.
    Multifactorial risk factor control in clinical practice and risk of cardiovascular disease in type 2 diabetes: report from the Swedish national diabetes register2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S493-S493Article in journal (Other academic)
  • 183.
    Eeg-Olofsson, K.
    et al.
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Med, S-41124 Gothenburg, Sweden..
    Ritsinger, V.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.;Reg Kronoberg, Dept Res & Dev, Vaxjo, Sweden..
    Hero, C.
    Gothenburg Univ, Sahlgrenska Univ Hosp, Dept Med, S-41124 Gothenburg, Sweden..
    Saleh, N.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Svensson, A. -M
    Norhammar, A.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Mortality by affected coronary artery vessels in 2776 patients with type 1 diabetes undergoing coronary angiography2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S577-S578Article in journal (Other academic)
  • 184. Eeg-Olofsson, Katarina
    et al.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Nilsson, Peter M
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Svensson, Ann-Marie
    Gudbjörnsdóttir, Soffia
    Eliasson, Björn
    Glycemic control and cardiovascular disease in 7,454 patients with type 1 diabetes: an observational study from the Swedish National Diabetes Register (NDR).2010In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 33, no 7, p. 1640-1646Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    We assessed the association between A1C and cardiovascular diseases (CVDs) in an observational study of patients with type 1 diabetes followed for 5 years.

    RESEARCH DESIGN AND METHODS

    A total of 7,454 patients were studied from the Swedish National Diabetes Register (aged 20-65 years, diabetes duration 1-35 years, followed from 2002 to 2007).

    RESULTS

    Hazard ratios (HRs) for fatal/nonfatal coronary heart disease (CHD) per 1% unit increase in baseline or updated mean A1C at Cox regression analysis were 1.31 and 1.34 and 1.26 and 1.32, respectively, for fatal/nonfatal CVD (all P < 0.001 after adjustment for age, sex, diabetes duration, blood pressure, total and LDL cholesterol, triglycerides, BMI, smoking, and history of CVD). HRs were only slightly lower for CHD (P = 0.002) and CVD (P = 0.002-0.007) after also adjusting for albuminuria. Adjusted 5-year event rates of CHD and CVD increased progressively with higher A1C, ranging from 5 to 12%, as well as when subgrouped by shorter (1-20 years) or longer (21-35 years) duration of diabetes. A group of 4,186 patients with A1C 5-7.9% (mean 7.2) at baseline showed risk reductions of 41% (95% confidence intervals: 15-60) (P = 0.005) for fatal/nonfatal CHD and 37% (12-55) (P = 0.008) for CVD, compared with 3,268 patients with A1C 8-11.9% (mean 9.0), fully adjusted also for albuminuria.

    CONCLUSIONS

    This observational study of patients in modern everyday clinical practice demonstrates progressively increasing risks for CHD and CVD with higher A1C, independently of traditional risk factors, with no J-shaped risk curves. A baseline mean A1C of 7.2% showed considerably reduced risks of CHD and CVD compared with A1C 9.0%, emphasizing A1C as a strong independent risk factor in type 1 diabetes.

  • 185. Eeg-Olofsson, Katarina
    et al.
    Gudbjornsdottir, Soffia
    Eliasson, Bjorn
    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.
    The triglycerides-to-HDL-cholesterol ratio and cardiovascular disease risk in obese patients with type 2 diabetes: An observational study from the Swedish National Diabetes Register (NDR)2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 106, no 1, p. 136-144Article in journal (Refereed)
    Abstract [en]

    Aims: Assessing the association between BMI and risk of coronary heart disease (CHD), cardiovascular disease (CVD) and mortality in patients with type 2 diabetes, also with regard to higher or lower levels of the ratio triglycerides-to-HDL-cholesterol (TG:HDL). Methods: 54,061 patients with BMI >= 18.5 kg/m(2), mean age and duration 61.5 +/- 8 and 6.9 +/- 6 years, 59% males, 14% with CVD history, from the Swedish National Diabetes Register, followed for mean 4.8 years. Results: Adjusting at Cox regression for non-BMI-linked (age, sex, smoking, CVD history) and BMI-linked (blood lipids, blood pressure, HbA1c, albuminuria) covariates, hazard ratios (HR) for fatal/nonfatal CHD and CVD were mainly increased with prominent obesity (BMI >= 35 kg/m(2)), 1.19 (p = 0.01) and 1.17 (p = 0.009), compared to normal weight (BMI 18.5-24.9 kg/m(2)), although increased also with obesity (BMI 30-34.9 kg/m(2)), 1.34 and 1.30 (p < 0.001), when adjusting only for non-BMI-linked covariates. Stratifying by 75th percentile of TG: HDL, with normal weight and TG: HDL < 1.9 as reference, obese and prominently obese with TG: HDL >= 1.9 had considerably increased HR around 1.7 for fatal/nonfatal CHD and 1.6 for CVD (p < 0.001), while obese and prominently obese with TG: HDL < 1.9 only had HR 1.2-1.3 for CHD and CVD (p 0.003-<0.01). Conclusion: Obese T2D patients with high TG: HDL, associated with increased insulin resistance, had considerably increased risk of CHD and CVD.

  • 186.
    Eeg-Olofsson, Katarina
    et al.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Med Prod Agcy, Uppsala, Sweden..
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Eliasson, Bjorn
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    Svensson, Ann-Marie
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Gothenburg, Sweden..
    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.
    Considerably decreased risk of cardiovascular disease with combined reductions in HbA1c, blood pressure and blood lipids in type 2 diabetes: Report from the Swedish National Diabetes Register2016In: Diabetes & Vascular Disease Research, ISSN 1479-1641, E-ISSN 1752-8984, Vol. 13, no 4, p. 268-277Article in journal (Refereed)
    Abstract [en]

    Objectives: Assess the effect of risk factors changes on risk for cardiovascular disease and mortality in patients with type 2 diabetes selected from the Swedish National Diabetes Register. Methods: Observational study of 13,477 females and males aged 30-75years, with baseline HbA1c 41-67mmol/mol, systolic blood pressure 122-154mmHg and ratio non-HDL:HDL 1.7-4.1, followed for mean 6.5years until 2012. Four groups were created: a reference group (n=6757) with increasing final versus baseline HbA1c, systolic blood pressure and non-HDL:HDL cholesterol during the study period, and three groups with decreasing HbA1c (n=1925), HbA1c and systolic blood pressure (n=2050) or HbA1c and systolic blood pressure and non-HDL:HDL (n=2745). Results: Relative risk reduction for fatal/nonfatal cardiovascular disease was 35% with decrease in HbA1c only (mean 6 to final 49mmol/mol), 56% with decrease in HbA1c and systolic blood pressure (mean 12 to final 128mmHg) and 75% with combined decreases in HbA1c, systolic blood pressure and non-HDL:HDL (mean 0.8 to final 2.1), all p<0.001 adjusting for clinical characteristics, other risk factors, treatments and previous cardiovascular disease. Similar risk reductions were found for fatal/nonfatal coronary heart disease, fatal cardiovascular disease, all-cause mortality and also in a subgroup of 3038 patients with albuminuria. Conclusion: Considerable risk reductions for cardiovascular disease and mortality were seen with combined long-term risk factor improvement.

  • 187.
    Ehrlund, Anna
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Mejhert, Niklas
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Bjork, Christel
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Andersson, Robin
    Univ Copenhagen, Dept Biol, Bioinformat Ctr, Copenhagen, Denmark;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Kulyte, Agne
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Astrom, Gaby
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Itoh, Masayoshi
    RIKEN Prevent Med & Diag Innovat Program, Wako, Saitama, Japan;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Kawaji, Hideya
    RIKEN Prevent Med & Diag Innovat Program, Wako, Saitama, Japan;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Lassmann, Timo
    Telethon Kids Inst, Perth, WA, Australia;Univ Western Australia, Perth, WA, Australia;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Daub, Carsten O.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;Karolinska Inst, Sci Life Lab, Stockholm, Sweden.
    Carninci, Piero
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Forrest, Alistair R. R.
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Hayashizaki, Yoshihide
    RIKEN Prevent Med & Diag Innovat Program, Wako, Saitama, Japan;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Sandelin, Albin
    Univ Copenhagen, Dept Biol, Bioinformat Ctr, Copenhagen, Denmark;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Ryden, Mikael
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Laurencikiene, Jurga
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Arner, Peter
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Arner, Erik
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan;Karolinska Inst, Dept Med, Stockholm, Sweden;RIKEN Omics Sci Ctr, Yokohama, Kanagawa, Japan.
    Transcriptional Dynamics During Human Adipogenesis and Its Link to Adipose Morphology and Distribution2017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 1, p. 218-230Article in journal (Refereed)
    Abstract [en]

    White adipose tissue (WAT) can develop into several phenotypes with different pathophysiological impact on type 2 diabetes. To better understand the adipogenic process, the transcriptional events that occur during in vitro differentiation of human adipocytes were investigated and the findings linked to WAT phenotypes. Single molecule transcriptional profiling provided a detailed map of the expressional changes of genes, enhancers, and long noncoding RNAs, where different types of transcripts share common dynamics during differentiation. Common signatures include early downregulated, transient, and late induced transcripts, all of which are linked to distinct developmental processes during adipogenesis. Enhancers expressed during adipogenesis overlap significantly with genetic variants associated with WAT distribution. Transiently expressed and late induced genes are associated with hypertrophic WAT (few but large fat cells), a phenotype closely linked to insulin resistance and type 2 diabetes. Transcription factors that are expressed early or transiently affect differentiation and adipocyte function and are controlled by several well-known upstream regulators such as glucocorticosteroids, insulin, cAMP, and thyroid hormones. Taken together, our results suggest a complex but highly coordinated regulation of adipogenesis.

  • 188. Ekström, N.
    et al.
    Miftaraj, M.
    Svensson, A. -M
    Sundell, K. Andersson
    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.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gudbjörnsdottir, S.
    Eliasson, B.
    Glucose-lowering treatment and clinical results in 163 121 patients with type 2 diabetes: an observational study from the Swedish national diabetes register2012In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 14, no 8, p. 717-726Article in journal (Refereed)
    Abstract [en]

    Aims: To analyse clinical characteristics and treatment results in unselected type 2 diabetes mellitus (T2DM) patients, with non-pharmacological treatment as well as the most commonly used pharmacological glucose-lowering treatment regimens, in everyday clinical practice. Methods: In this population-based cross-sectional study, information was linked from the Swedish National Diabetes Register, Prescribed Drug Register and Patient Register. T2DM patients with non-pharmacological treatment and T2DM patients continuously using the 12 most common pharmacological treatment regimens were included in the study (n = 163121). Results: There were statistically significant differences in clinical characteristics between the groups. Patients with insulin-based treatment regimens had the longest duration of diabetes and more cardiovascular risk factors than the T2DM-population in general. The proportion of patients reaching HbA1c =7% varied between 70.1% (metformin) and 25.0% [premixed insulin (PMI) + SU) in patients with pharmacological treatment. 84.8% of the patients with non-pharmacological treatment reached target. Compared to patients on metformin, patients on other pharmacological treatments had a lower likelihood, with hazard ratios ranging from 0.58; 95% confidence interval (CI), 0.540.63 to 0.97;0.940.99, of having HbA1c =7% (adjusted for covariates). Patients on insulin-based treatments had the lowest likelihood, while non-pharmacological treatment was associated with an increased likelihood of having HbA1c =7%. Conclusion: This nation-wide study shows insufficiently reached treatment goals for haemoglobin A1c (HbA1c) in all treatment groups. Patients on insulin-based treatment regimens had the longest duration of diabetes, more cardiovascular risk factors and the highest proportions of patients not reaching HbA1c target.

  • 189. Ekström, Nils
    et al.
    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.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eliasson, Björn
    Fhärm, Eva
    Rolandsson, Olov
    Miftaraj, Mervete
    Svensson, Ann-Marie
    Gudbjörnsdottir, Soffia
    Aspirin treatment and risk of first incident cardiovascular diseases in patients with type 2 diabetes: an observational study from the Swedish National Diabetes Register.2013In: BMJ open, ISSN 2044-6055, Vol. 3, no 4Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the benefits and risks associated with aspirin treatment in patients with type 2 diabetes and no previous cardiovascular disease (CVD) in clinical practice.

    DESIGN: Population-based cohort study between 2005 and 2009, mean follow-up 3.9 years.

    SETTING: Hospital outpatient clinics and primary care in Sweden.

    PARTICIPANTS: Men and women with type 2 diabetes, free from CVD, including atrial fibrillation and congestive heart failure, at baseline, registered in the Swedish National Diabetes Register, with continuous low-dose aspirin treatment (n=4608) or no aspirin treatment (n=14 038).

    MAIN OUTCOME MEASURES: Risks of CVD, coronary heart disease (CHD), stroke, mortality and bleedings, associated with aspirin compared with no aspirin, were analysed in all patients and in subgroups by gender and estimated cardiovascular risk. Propensity scores were used to adjust for several baseline risk factors and characteristics at Cox regression, and the effect of unknown covariates was evaluated in a sensitivity analysis.

    RESULTS: There was no association between aspirin use and beneficial effects on risks of CVD or death. Rather, there was an increased risk of non-fatal/fatal CHD associated with aspirin; HR 1.19 (95% CI 1.01 to 1.41), p=0.04. The increased risk of cardiovascular outcomes associated with aspirin was seen when analysing women separately; HR 1.41 (95% CI 1.07 to 1.87), p=0.02, and HR 1.28 (95% CI 1.01 to 1.61), p=0.04, for CHD and CVD, respectively, but not for men separately. There was a trend towards increased risk of a composite of bleedings associated with aspirin, n=157; HR 1.41 (95% CI 0.99 to 1.99).

    CONCLUSIONS: The results support the trend towards more restrictive use of aspirin in patients with type 2 diabetes and no previous CVD. More research is needed to explore the differences in aspirin's effects in women and men.

  • 190. Ekström, Nils
    et al.
    Schiöler, Linus
    Svensson, Ann-Marie
    Eeg-Olofsson, Katarina
    Miao Jonasson, Junmei
    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.
    Eliasson, Björn
    Gudbjörnsdottir, Soffia
    Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 4, p. e001076-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    To evaluate the effectiveness and safety of metformin use in clinical practice in a large sample of pharmacologically treated patients with type 2 diabetes and different levels of renal function.

    DESIGN

    Observational study between July 2004 and December 2010, mean follow-up 3.9 years.

    SETTING

    Hospital outpatient clinics and primary care in Sweden.

    PARTICIPANTS

    51 675 men and women with type 2 diabetes, registered in the Swedish National Diabetes Register, and on continuous glucose-lowering treatment with oral hypoglycaemic agents (OHAs) or insulin.

    MAIN OUTCOME MEASURES

    Risks of cardiovascular disease (CVD), all-cause mortality and acidosis/serious infection, associated with each treatment regimens, were analysed in all patients and in subgroups with different estimated glomerular filtration rate (eGFR) intervals. Covariance adjustment and propensity scores were used to adjust for several baseline risk factors and characteristics at Cox regression.

    RESULTS

    Compared with metformin in monotherapy, HRs for fatal/non-fatal CVD and all-cause mortality with all other OHAs combined (approximately 80% sulphonylureas) in monotherapy were 1.02 (95% CI 0.93 to 1.12) and 1.13 (1.01 to 1.27), while 1.18 (1.07 to 1.29) and 1.34 (1.19 to 1.50) with insulin in monotherapy, adjusting using propensity scores. Metformin, compared with any other treatment, showed reduced risks of acidosis/serious infection (adjusted HR 0.85, 95% CI 0.74 to 0.97) and all-cause mortality (HR 0.87, 95% CI 0.77 to 0.99), in patients with eGFR 45-60 ml/min/1.73 m(2), and no increased risks of all-cause mortality, acidosis/serious infection or CVD were found in patients with eGFR 30-45 ml/min/1.73 m(2).

    CONCLUSIONS

    Metformin showed lower risk than insulin for CVD and all-cause mortality and slightly lower risk for all-cause mortality compared with other OHA, in these 51 675 patients followed for 4 years. Patients with renal impairment showed no increased risk of CVD, all-cause mortality or acidosis/serious infection. In clinical practice, the benefits of metformin use clearly outbalance the risk of severe side effects.

  • 191. Ekström, Nils
    et al.
    Svensson, Ann-Marie
    Miftaraj, Mervete
    Andersson Sundell, Karolina
    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.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eliasson, Björn
    Gudbjörnsdottir, Soffia
    Durability of oral hypoglycemic agents in drug naïve patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR)2015In: BMJ open diabetes research & care, ISSN 2052-4897, Vol. 3, article id e000059Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To analyze the durability of monotherapy with different classes of oral hypoglycemic agents (OHAs) in drug naïve patients with type 2 diabetes mellitus (T2DM) in real life.

    METHODS: Men and women with T2DM, who were new users of OHA monotherapy and registered in the Swedish National Diabetes Register July 2005-December 2011, were available (n=17 309) and followed for up to 5.5 years. Time to monotherapy failure, defined as discontinuation of continuous use with the initial agent, switch to a new agent, or add-on treatment of a second agent, was analyzed as a measure of durability. Baseline characteristics were balanced by propensity score matching 1:5 between groups of sulfonylurea (SU) versus metformin (n=4303) and meglitinide versus metformin (n=1308). HRs with 95% CIs were calculated using Cox regression models.

    RESULTS: SU and meglitinide, as compared with metformin, were associated with increased risk of monotherapy failure (HR 1.74; 95% CI 1.56 to 1.94 and 1.66; 1.37 to 2.00 for SU and meglitinide, respectively). When broken down by type of monotherapy failure, SU and meglitinide were associated with an increased risk of add-on treatment of a second agent (HR 3.14; 95% CI 2.66 to 3.69 and 2.52; 1.89 to 3.37 for SU and meglitinide, respectively) and of switch to a new agent (HR 2.81; 95% CI 2.01 to 3.92 and 3.78; 2.25 to 6.32 for SU and meglitinide, respectively). The risk of discontinuation did not differ significantly between the groups.

    CONCLUSIONS: In this nationwide observational study reflecting clinical practice, SU and meglitinide showed substantially increased risk of switch to a new agent or add on of a second agent compared with metformin. These results indicate superior glycemic durability with metformin compared with SU and also meglitinide in real life.

  • 192.
    Ekström, Nils
    et al.
    Univ Gothenburg, Dept Med, Gothenburg, Sweden.;Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Svensson, Ann-Marie
    Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Miftaraj, Mervete
    Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Franzen, Stefan
    Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Med Prod Agcy, Uppsala, Sweden..
    Eliasson, Bjorn
    Univ Gothenburg, Dept Med, Gothenburg, Sweden..
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Dept Med, Gothenburg, Sweden.;Ctr Registers Reg Vastra Gotaland, Gothenburg, Sweden..
    Cardiovascular safety of glucose-lowering agents as add-on medication to metformin treatment in type 2 diabetes: report from the Swedish National Diabetes Register2016In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 18, no 10, p. 990-998Article in journal (Refereed)
    Abstract [en]

    Aim: To investigate the relative safety of various glucose-lowering agents as add-on medication to metformin in type 2 diabetes in an observational study linking five national health registers. Research design and methods: Patients with type 2 diabetes who had been on metformin monotherapy and started another agent in addition to metformin were eligible for inclusion. The study period was 2005-2012. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, cardiovascular disease (CVD), coronary heart disease (CHD), stroke and congestive heart failure (CHF) were estimated using Cox proportional hazards models, weighted for a propensity score. Results: Of the 20 422 patients included in the study, 43% started on second-line treatment with sulphonylurea (SU), 21% basal insulin, 12% thiazolidinedione (TZD), 11% meglitinide, 10% dipeptidyl peptidase-4 (DPP-4) inhibitor, 1% glucagon-like peptide-1 (GLP-1) receptor agonist and 1% acarbose. At the index date, the mean patient age was similar to 60 years for all groups except the GLP-1 receptor agonist (56.0 years) and SU (62.9 years) groups. Diabetes duration and glycated haemoglobin levels were similar in all groups. When compared with SU, basal insulin was associated with an 18% higher risk and TZD with a 24% lower risk of mortality [HR 1.18 (95% CI 1.03-1.36) and 0.76 (95% CI 0.62-0.94)], respectively. DPP-4 inhibitor treatment was associated with significantly lower risks of CVD, fatal CVD, CHD, fatal CHD and CHF. Conclusions: This nationwide observational study showed that second-line treatment with TZD and DPP-4 inhibitor as add-on medication to metformin were associated with significantly lower risks of mortality and cardiovascular events compared with SU, whereas basal insulin was associated with a higher risk of mortality.

  • 193. Eliasson, B
    et al.
    Gudbjörnsdottir, S
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eeg-Olofsson, K
    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.
    LDL-cholesterol versus non-HDL-to-HDL-cholesterol ratio and risk for coronary heart disease in type 2 diabetes2014In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 21, no 11, p. 1420-1428Article in journal (Refereed)
    Abstract [en]

    AIMS: We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD), which has been less analysed previously in type 2 diabetes.

    DESIGN, METHODS: Observational study of 46,786 patients with type 2 diabetes, aged 30-70 years, from the Swedish National Diabetes Register, followed for a mean of 5.8 years until 2009. Baseline and updated mean low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-, non-HDL-cholesterol, and non-HDL-to-HDL-cholesterol ratio were measured.

    RESULTS: Hazard ratios (HR) for CHD with quartiles 2-4 of baseline lipid measures, with lowest quartile 1 as reference: 1.03-1.29-1.63 for LDL; 1.23-1.41-1.95 for non-HDL; 1.29-1.39-1.57 for HDL; and 1.31-1.67-2.01 for non-HDL:HDL, all p < 0.001 except for quartile 2 of LDL, when adjusted for clinical characteristics and nonlipid risk factors. A similar picture was seen with updated mean values. Splines with absolute 6-year CHD rates in a Cox model showed decreasing rates only down to around 3 mmol/l for LDL, with linearly decreasing rates to the lowest level of non-HDL:HDL.Non-HDL and HDL were independent additive risk factors for CHD risk. HRs per 1 SD continuous decrease in baseline or updated mean HDL were 1.14-1.17 when fully adjusted as above, and 1.08-1.13 when also adjusted for non-HDL (p < 0.001). HRs were 1.13-1.16 adjusted for LDL, and 1.22-1.26 adjusted for total cholesterol and triglycerides (p < 0.001). Splines showed progressively increasing 6-year CHD rates with lower HDL down to 0.5 mmol/l.

    CONCLUSIONS: This study suggests that lower levels of non-HDL:HDL are a better risk marker for CHD than LDL-cholesterol below 3 mmol/l.

  • 194.
    Eltom, Mohamed A.
    et al.
    Mulazmin Diabet Ctr, Khartoum, Sudan.;Ahfad Univ Women, Khartoum, Sudan..
    Mohamed, Abubakr H. Babiker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Mulazmin Diabet Ctr, Khartoum, Sudan.;Ahfad Univ Women, Khartoum, Sudan..
    Elrayah-Eliadarous, Hind
    Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy, Stockholm, Sweden..
    Yassin, Kamal
    Mulazmin Diabet Ctr, Khartoum, Sudan.;Ahfad Univ Women, Khartoum, Sudan..
    Noor, Sufian K.
    Nile Valley Univ, Dept Med, Fac Med & Hlth Sci, Khartoum, Sudan..
    Elmadhoun, Wadie M.
    Nile Valley Univ, Dept Med, Fac Med & Hlth Sci, Khartoum, Sudan..
    Ahmed, Mohamed H.
    Milton Keynes Univ Hosp NHS Fdn Trust, Dept Med, Milton Keynes, Bucks, England.;Milton Keynes Univ Hosp NHS Fdn Trust, HIV Metab Clin, Milton Keynes, Bucks, England..
    Increasing prevalence of type 2 diabetes mellitus and impact of ethnicity in north Sudan2018In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 136, p. 93-99Article in journal (Refereed)
    Abstract [en]

    Background: Diabetes mellitus constitutes a global health threat, with increasing burden of disease in low and middle-income countries witnessing ongoing epidemiological transition including Sudan.

    Aims: To study the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes and determine the relationship to gender, age, waist circumference, body mass index, residence and ethnicity among the adult population in north Sudan.

    Methods: A cross-sectional, population-based study in Northern State and River Nile State using random multi-stage cluster sampling targeting 5376 participants from 14 localities divided into 60 urban and 40 rural clusters. In each cluster, 60 households were studied. Blood glucose level and anthropometric measurements were recorded and a questionnaire containing demographic data was obtained from each participant.

    Results: The prevalence of T2DM among participants was 18.7% and prediabetes was 12.9%. Among people living with T2DM, 694(71.0%) were known cases of T2DM, whereas 284 (29.0%) were newly diagnosed cases. The significant associated risk factors for T2DM included urban residence (AOR 1.23, 95% CI 1.09-1.41), age above 60 years (AOR 4.77, 95% CI 4.04-5.63), obese BMI (AOR 1.26, 95% CI 1.03-1.55) and central obesity (AOR 1.39, 95% CI 1.14-1.68). Compared to indigenous population, individuals of Egyptian descents (AOR 1.28, 95% CI 1.04-1.57) and mixed origin (AOR 1.24, 95% CI 1.04-1.48) had increased risk of T2DM.

    Conclusion: The prevalence of T2DM and prediabetes in north Sudan have increased significantly since 1996 with variations between ethnicities which showed to be an independent risk factor for T2DM. Health authorities are recommended to set plans to meet the health needs of these communities.

  • 195.
    Englund Flodström, I
    et al.
    Department of Medical Biosciences, Umeå University,.
    Berggren, Karl
    Department of Laboratory Medicine, Unilabs, Sweden.
    Usener, B
    Department of Laboratory Medicine, Unilabs, Sweden.
    Broberg, H
    Department of Laboratory Medicine, Unilabs, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Brattsand, Göran
    Department of Medical Biosciences, Umeå University,.
    The Effect of Thyroid Dysfunction on Plasma Creatinine Levels2016In: Annals of Thyroid Research, Vol. 2, no 2, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Introduction: There are conflicting reports on how kidney function isaffected in patients with thyroid dysfunction. This study was designed toinvestigate how hypothyroidism and hyperthyroidism affect the concentration ofplasma creatinine in a large patient material.

    Methods: Patient results with simultaneous determinations of FT4, FT3,TSH and creatinine were extracted from the laboratory information system. Overan eight year period this yielded more than thousand cases with results fromthyroid function tests combined with plasma creatinine concentrations.

    Results: Median plasma levels of creatinine differed significantly inhypothyroid and hyperthyroid patients as compared to euthyroid controls.An approximate 20% increase and decrease in median plasma creatinineconcentration was found for hypothyroid and hyperthyroid patients, respectively.The differences were statistically significant (p<0.001) for both groups and stillso when divided according to gender. A correlation analysis showed a significantnegative correlation between the biologically active freeT3 and creatinine.

    Conclusion: Thyroid hormone correlates significantly to plasma creatinine.It is important to be aware of the relationship between thyroid function andkidney function when interpreting plasma creatinine results and to considerhypothyroidism or hyperthyroidism as a possible cause of an abnormal plasmacreatinine level.Further research is needed in order to uncover the mechanisms behi

  • 196.
    Engman, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA..
    Linnman, Clas
    Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA.;Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA..
    Van Dijk, Koene R. A.
    Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA.;Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA..
    Milad, Mohammed R.
    Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA..
    Amygdala subnuclei resting-state functional connectivity sex and estrogen differences2016In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 63, p. 34-42Article in journal (Refereed)
    Abstract [en]

    The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centro-medial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion.

  • 197.
    Engskog, Mikael K. R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Med Prod Agcy, Dag Hammarskjolds Vag 42,Box 26, SE-75103 Uppsala, Sweden..
    Pettersson, Curt
    LC-MS based global metabolite profiling: the necessity of high data quality2016In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 7, article id 114Article, review/survey (Refereed)
    Abstract [en]

    LC-MS based global metabolite profiling currently lacks detailed guidelines to demonstrate that the obtained data is of high enough analytical quality. Insufficient data quality may result in the failure to generate a hypothesis, or in the worst case, a false or skewed hypothesis. After assessing the literature, it is apparent that an analytically focused summary and critical discussion related to this subject would be beneficial for both beginners and experts engaged in this field. A particular focus will be placed on data quality, which we here define as the degree to which a set of parameters fulfills predetermined criteria, similar to the established guidelines for targeted analysis. However, several of these parameters are difficult to assess since holistic approaches measure thousands of metabolites in parallel and seldom include predefined knowledge of which metabolites will differ between sample groups. In this review, the following parameters will be discussed in detail: reproducibility, selectivity, certainty of metabolite identification and metabolite coverage. The review systematically describes the generic workflow for LC-MS based global metabolite profiling and highlights how each separate part may affect data quality. The last part of the review describes how data quality can be evaluated as well as identifies areas where additional improvement is needed. In this review, we provide our own analytical opinions in regards to evaluation and, to some extent, improvement of data quality.

  • 198.
    Engström, Maria Svedbo
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg; Dalarna Univ, Sch Educ Hlth & Social Studies, Falun.
    Leksell, Janeth
    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.
    Johansson, Unn-Britt
    Sophiahemmet Univ, Stockholm; Karolinska Inst, Dept Clin Sci & Educ, Södersjukhuset, Stockholm.
    Eeg-Olofsson, Katarina
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg; Sahlgrens Univ Hosp, Gothenburg.
    Borg, Sixten
    Lund Univ, Dept Clin Sci Malmo, Hlth Econ Unit, Lund.
    Palaszewski, Bo
    Dept Data Management & Anal, Region Västra Götaland, Gothenburg.
    Gudbjornsdottir, Soffia
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg; Register Ctr Västra Götaland, Gothenburg, Sweden..
    A disease-specific questionnaire for measuring patient-reported outcomes and experiences in the Swedish National Diabetes Register: Development and evaluation of content validity, face validity, and test-retest reliability2018In: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 101, no 1, p. 139-146Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the development and evaluation of the content and face validity and test-retest reliability of a disease-specific questionnaire that measures patient-reported outcomes and experiences for the Swedish National Diabetes Register for adult patients who have type 1 or type 2 diabetes.

    Methods: In this methodological study, a questionnaire was developed over four phases using an iterative process. Expert reviews and cognitive interviews were conducted to evaluate content and face validity, and a postal survey was administered to evaluate test-retest reliability.

    Results: The expert reviews and cognitive interviews found the disease-specific questionnaire to be understandable, with relevant content and value for diabetes care. An item-level content validity index ranged from 0.6-1.0 and a scale content validity/average ranged from 0.7-1.0. The fourth version, with 33 items, two main parts and seven dimensions, was answered by 972 adults with type 1 and type 2 diabetes (response rate 61%). Weighted Kappa values ranged from 0.31-0.78 for type 1 diabetes and 0.27-0.74 for type 2 diabetes.

    Conclusions: This study describes the initial development of a disease-specific questionnaire in conjunction with the NDR. Content and face validity were confirmed and test-retest reliability was satisfactory. Practice implications: With the development of this questionnaire, the NDR becomes a clinical tool that contributes to further understanding the perspectives of adult individuals with diabetes.

  • 199.
    Engström, Maria Svedbo
    et al.
    Gothenburg Univ, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.;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. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden..
    Johansson, Unn-Britt
    Sophiahemmet Univ, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden..
    Gudbjörnsdottir, Soffia
    Gothenburg Univ, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.;Register Ctr Vastra Gotaland, Gothenburg, Sweden..
    What is important for you?: A qualitative interview study of living with diabetes and experiences of diabetes care to establish a basis for a tailored Patient-Reported Outcome Measure for the Swedish National Diabetes Register2016In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 3, article id e010249Article in journal (Refereed)
    Abstract [en]

    Objectives There is a growing emphasis on the perspective of individuals living with diabetes and the need for a more person-centred diabetes care. At present, the Swedish National Diabetes Register (NDR) lacks patient-reported outcome measures (PROMs) based on the perspective of the patient. As a basis for a new PROM, the aim of this study was to describe important aspects in life for adult individuals with diabetes. Design Semistructured qualitative interviews analysed using content analysis. Setting Hospital-based outpatient clinics and primary healthcare clinics in Sweden. Participants 29 adults with type 1 diabetes mellitus (DM) (n=15) and type 2 DM (n=14). Inclusion criteria: Swedish adults (18years) living with type 1 DM or type 2 DM (duration 5years) able to describe their situation in Swedish. Purposive sampling generated heterogeneous characteristics. Results To live a good life with diabetes is demanding for the individual, but experienced barriers can be eased by support from others in the personal sphere, and by professional support from diabetes care. Diabetes care was a crucial resource to nurture the individual's ability and knowledge to manage diabetes, and to facilitate life with diabetes by supplying support, guidance, medical treatment and technical devices tailored to individual needs. The analysis resulted in the overarching theme To live a good life with diabetes' constituting the two main categories How I feel and how things are going with my diabetes' and Support from diabetes care in managing diabetes' including five different categories. Conclusions Common aspects were identified including the experience of living with diabetes and support from diabetes care. These will be used to establish a basis for a tailored PROM for the NDR.

  • 200.
    Engström, Sevek
    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.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gahnberg, Lars
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Effectiveness of screening for diabetes mellitus in dental health care2013In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 30, no 2, p. 239-245Article in journal (Refereed)
    Abstract [en]

    Aims:  The aim of the present study was to test the effectiveness of opportunistic blood glucose screening in a cooperational framework between dental and primary health care.

    Methods:  Altogether, 1568 subjects, age 20-75 years, with no previous history of diabetes, who came for a regular dental examination, had their non-fasting blood glucose measured with a portable blood glucose meter. Subjects with a concentration of ≥ 6.7 mmol/l (121 mg dl(-1) ) were referred to their primary healthcare centre for follow-up. The outcome, a diagnosis of diabetes mellitus, was obtained from primary healthcare centre and hospital patient records, during 3 years after screening.

     Results:  Of the 155 (9.9%) subjects who screened positive, 139 (89.7%) came to their primary healthcare centre within the 3-year follow-up period and nine (5.8%) were diagnosed as having diabetes mellitus according to the World Health Organization criteria. Of the 1413 subjects who screened negative, 1137 (80.5%) came to the primary healthcare centre and eight (0.6%) were found to have diabetes mellitus. Screening sensitivity was 52.9%, specificity 90.6% and positive predictive value 5.8%. The number of subjects needed to screen to find one case of diabetes was 196. Delineating the study population to those 40- to 75-year-olds with a BMI ≥ 25 kg/m(2) , and 30-to 75-year-olds with a BMI ≥ 30 kg/m(2) , the numbers needed to screen was reduced to 96.

    Conclusions:  Cooperation between dental and primary care for high blood glucose screening and follow-up appears to be a feasible method for early diagnosis of diabetes.

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