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oai:gupea.ub.gu.se:2077/448642016-11-03T02:34:06Zcom_2077_283com_2077_17com_2077_10556col_2077_543col_2077_310col_2077_10557

Åberg, Daniel 2016-11-02T10:20:18Z 2016-11-02T10:20:18Z 2016-11-02 978-91-628-9917-2 (print) 978-91-628-9918-9 (pdf) http://hdl.handle.net/2077/44864 Background and aims: Insulin, insulin-like growth factor-I (IGF-I), and the six high-affinity IGF-binding proteins (IGFBPs) play an important role in growth, metabolism and regeneration throughout the entire life span. In contrast, the role of IGF-II in adult life has been unclear. Animal studies have demonstrated that altered brain activity of the insulin/IGF-system is associated with reduced cognitive function and worse outcome after experimentally induced stroke and this is reversed by IGF-I-treatment. The overall aim of this thesis was to determine whether the insulin/IGF-I system is of importance for outcome of ischemic stroke (IS) also in humans and whether insulin and insulin-like peptides are dysregulated in patients with Alzheimer’s disease (AD). Patients and methods: Two well-characterized clinical cohorts were studied. In SAHLSIS (Sahlgrenska Academy Study on Ischemic Stroke; originally 600 IS patients and 600 population-based controls), characterization of patients after IS included serum samples and stroke scales. Furthermore, serum and cerebrospinal fluid (CSF) levels of insulin, IGF-I, and IGF-II were determined in a cross-sectional study of patients (n=60) with AD and other forms of cognitive impairment, and healthy controls (n=20). Results: In Paper I, high serum IGF-I concentrations were associated with better improvement of functional independence in SAHLSIS. In Paper II, analyses of single-nucleotide polymorphisms (SNPs) in the IGF1 gene showed that the major allele of rs7136446 was associated with favorable post-stroke outcome after 2 years. In Paper III, insulin resistance was associated with functional outcome, especially in patients with cryptogenic stroke. In Paper IV, serum but not CSF levels of IGF-I were increased in patients with AD whereas insulin levels were unchanged both in serum and CSF. In Paper V, CSF IGF-II level was increased in male but not in female patients with AD. Conclusions: The IGF-I/insulin system is associated with functional outcome after ischemic stroke. Furthermore, levels of IGF-I and IGF-II are dysregulated in Alzheimer’s disease. eng I. Åberg D, Jood K, Blomstrand C, Jern C, Nilsson M, Isgaard J, Aberg ND. Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocrinol Metab. 2011:96:E1055-E1064. ::doi::10.1210/jc.2010-2802 II. Åberg ND, Olsson S, Åberg D, Jood K, Nilsson M, Blomstrand C, Svensson J, Isgaard J, Jern C. Genetic variation at the IGF1 locus shows association with post-stroke outcome and to circulating IGF1. Eur J Endocrinol. 2013:169:759-765. ::doi::10.1530/EJE-13-0486 III. Åberg D, Åberg ND, Jood K, Holmegaard L, Redfors P, Blomstrand C, Isgaard J, Jern C, Svensson J. Insulin resistance and outcome of ischemic stroke. 2016: manuscript. IV. Johansson P, Åberg D, Johansson J-O, Mattsson N, Hansson O, Ahrén B, Isgaard J, Åberg ND, Blennow K, Zetterberg H, Wallin A, Svensson J. Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer´s disease. Psychoneuroendocrinology. 2013:38:1729-1737. ::doi::10.1016/j.psyneuen.2013.02.006 V. Åberg D, Johansson P, Isgaard J, Wallin A, Johansson J-O, Andreasson U, Blennow K, Zetterberg H, Åberg ND, Svensson J. Increased cerebrospinal fluid level of insulin-like growth factor-II (IGF-II) in male patients with Alzheimer’s Disease. J Alzheimers Dis. 2015:48:637-646. ::doi:: 10.3233/JAD-150351 Ischemic Stroke (IS) Alzheimer´s disease (AD) Cognitive Impairment Dementia Insulin-like Growth Factor I (IGF-I) The Role of Insulin and Insulin-like Ischemic Stroke and Cognitive Impairment text Doctoral thesis Doctor of Philosophy (Medicine) daniel.aberg@medic.gu.se University of Gothenburg. Sahlgrenska Academy Inst of Medicine. Department of Internal Medicine and Clinical Nutrition Fredagen den 25 november 2016, kl 13.00, Hörsal Ivan Ivarsson, Medicinaregatan 3, Göteborg 2016-11-25 SA open.access