title: STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation.
abstract: OBJECTIVE
  STEAP4 (six-transmembrane epithelial antigen of the prostate 4) is a metalloreductase that has been shown previously to protect cells from inflammatory damage. Genetic variants in STEAP4 have been associated with numerous metabolic disorders related to obesity, including putative defects in the acute insulin response to glucose in type 2 diabetes.
  
  
  OBJECTIVE
  We examined whether obesity and/or type 2 diabetes altered STEAP4 expression in human pancreatic islets.
  
  
  METHODS
  Human islets were isolated from deceased donors at two medical centers and processed for quantitative polymerase chain reaction. Organ donors were selected by status as non-diabetic or having type 2 diabetes. Site 1 (Edmonton): N = 13 type 2 diabetes donors (7M, 6F), N = 20 non-diabetic donors (7M, 13F). Site 2 (Virginia): N = 6 type 2 diabetes donors (6F), N = 6 non-diabetic donors (3M, 3F).
  
  
  RESULTS
  STEAP4 showed reduced islet expression with increasing body mass index among all donors (P < 0.10) and non-diabetic donors (P < 0.05) from Site 1; STEAP4 showed reduced islet expression among type 2 diabetes donors with increasing hemoglobin A1c. Islet STEAP4 expression was also marginally higher in female donors (P < 0.10). Among type 2 diabetes donors from Site 2, islet insulin expression was reduced, STEAP4 expression was increased, and white blood cell counts were increased compared to non-diabetic donors. Islets from non-diabetic donors that were exposed overnight to 5 ng/ml IL-1β displayed increased STEAP4 expression, consistent with STEAP4 upregulation by inflammatory signaling.
  
  
  CONCLUSIONS
  These findings suggest that increased STEAP4 mRNA expression is associated with inflammatory stimuli, whereas lower STEAP4 expression is associated with obesity in human islets. Given its putative protective role, downregulation of STEAP4 by chronic obesity suggests a mechanism for reduced islet protection against cellular damage.
authors.affiliation: Department of Biomedical Sciences, Ohio University, Athens, OH, USA.|Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Gordon
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Majithia
authors.affiliation: Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, T6G 2R3, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, T6G 2R3, Canada.
authors.forename: Jocelyn E Manning
authors.initials: JEM
authors.lastname: Fox
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Frances L
authors.initials: FL
authors.lastname: Byrne
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Langman
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Brayman
authors.affiliation: Department of Biomedical Sciences, Ohio University, Athens, OH, USA. nunemake@ohio.edu.|Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA. nunemake@ohio.edu.
authors.forename: Craig S
authors.identifier: http://orcid.org/0000-0003-2894-3388
authors.initials: CS
authors.lastname: Nunemaker
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D006442:Glycated Hemoglobin; D008565:Membrane Proteins; D010088:Oxidoreductases; C517652:hemoglobin A1c protein, human; C503310:STEAP4 protein, human
keywords: Cytokines; Inflammation; Iron; Islets; Obesity; Type 2 diabetes