title: Metabolic changes in type 2 diabetes are reflected in peripheral blood cells, revealing aberrant cytotoxicity, a viral signature, and hypoxia inducible factor activity.
abstract: BACKGROUND
  Metabolic syndrome (MetS) is characterized by central obesity, insulin resistance, dysglycemia, and a pro-atherogenic plasma lipid profile. MetS creates a high risk for development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), presumably by altering inflammatory responses. Presently, it is unknown how the chronic metabolic disturbances in acute hyperglycemia, MetS and T2DM affect the immune activity of peripheral blood cells.
  
  
  METHODS
  We performed genome-wide expression analysis of peripheral blood cells obtained from patients with T2DM (n = 6) and age-, sex- , BMI- and blood pressure-matched obese individuals with MetS (n = 4) and lean healthy normoglycemic controls (n = 3), both under fasting conditions and after controlled induction of acute hyperglycemia during a 70 min hyperglycemic clamp. Differential gene expression during fasting conditions was confirmed by real-time PCR, for which we included additional age-, sex-, BMI-, and blood pressure-matched obese individuals with (n = 4) or without (n = 4) MetS.
  
  
  RESULTS
  Pathway and Gene ontology analysis applied to baseline expression profiles of peripheral blood cells from MetS and T2DM patients revealed metabolic changes, highly similar to a reoviral infection gene signature in T2DM patients. Transcription factor binding site analysis indicated that increased HIF-1α activity, a transcription factor induced by either hypoxia or oxidative stress, is responsible for this aberrant metabolic profile in peripheral blood cells from T2DM patients. Acute hyperglycemia in healthy controls resulted in reduced expression of cytotoxicity-related genes, representing NK- and CD8(+) cells. In obese controls, MetS and especially T2DM patients, baseline expression of genes involved in cytotoxicity was already low, compared to healthy controls and did not further decrease upon acute hyperglycemia.
  
  
  CONCLUSIONS
  The reduced activity of cytotoxic genes in T2DM is explained by chronic hyperglycemia, but its acute effects are restricted to healthy controls. Genome expression of circulating leukocytes from T2DM patients differs from MetS individuals by a specific reovirus signature. Our data thus suggest a role for suppressed anti-viral capacity in the etiology of diabetes.
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. t.vanderpouwkraan@vumc.nl.
authors.forename: Tineke C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. j.chen@vumc.nl.
authors.forename: Weena J
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. MCMBunck@vumc.nl.
authors.forename: Mathijs C M
authors.initials: MC
authors.lastname: Bunck
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. d.vanraalte@vumc.nl.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: van Raalte
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. NJ.vdZijl@vumc.nl.
authors.forename: Nynke J
authors.initials: NJ
authors.lastname: van der Zijl
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. r.vangenugten@vumc.nl.
authors.forename: Renate E
authors.initials: RE
authors.lastname: van Genugten
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. l.vanbloemendaal@vumc.nl.
authors.forename: Liselotte
authors.initials: L
authors.lastname: van Bloemendaal
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. JMC.Baggen@vumc.nl.
authors.forename: Josefien M
authors.initials: JM
authors.lastname: Baggen
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands. E.Serne@vumc.nl.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Serné
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands. aj.horrevoets@vumc.nl.
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
mesh_terms: D000368:Aged; D001794:Blood Pressure; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D015309:Glucose Clamp Technique; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012087:Reoviridae / Q000235:genetics*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008055:Lipids