The Role of Insulin and Insulin-like Ischemic Stroke and Cognitive Impairment
Abstract
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.
Parts of work
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
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Inst of Medicine. Department of Internal Medicine and Clinical Nutrition
Disputation
Fredagen den 25 november 2016, kl 13.00, Hörsal Ivan Ivarsson, Medicinaregatan 3, Göteborg
Date of defence
2016-11-25
daniel.aberg@medic.gu.se
Date
2016-11-02Author
Åberg, Daniel
Keywords
Ischemic Stroke (IS)
Alzheimer´s disease (AD)
Cognitive Impairment
Dementia
Insulin-like Growth Factor I (IGF-I)
Publication type
Doctoral thesis
ISBN
978-91-628-9917-2 (print)
978-91-628-9918-9 (pdf)
Language
eng