STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation
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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.
We examined whether obesity and/or type 2 diabetes altered STEAP4 expression in human pancreatic islets.
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).
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.
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.
KeywordsInflammation Islets Obesity Type 2 diabetes Cytokines Iron
Support for this work was provided by R01 DK089182 and the Ohio University Diabetes Institute to CSN; PEM holds a 2016/2017 Killam Professorship; funding for CEM from VA Grant 5I01BX001733 and R01 DK093954. We thank the Human Organ Procurement and Exchange (HOPE) program (Edmonton, Canada) and the Trillium Gift of Life Network (TGLN; Toronto, Canada) for assistance with procurement of donor pancreas for research. We thank Mr. James Lyon for human islet isolations performed at the Alberta Diabetes Institute IsletCore, supported by funding from the Alberta Diabetes Foundation, and Drs. Tatsuya Kin and James Shapiro for human islet isolations performed at the University of Alberta Clinical Islet Laboratory. We thank Dr. Tatsuyoshi Kono at Indiana University School of Medicine for technical assistance. We also thank The University of Virginia Department of Surgery and Human Islet Isolation GMP Facility. NIH DK089182 to CSN and Alberta Diabetes Foundation to PEM.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
All studies were approved by the Human Research Ethics Board at the University of Alberta (Pro00001754, Pro00013094) for donors from Site 1 and by University of Virginia Institutional Review Board approved protocol #14904 for donors from Site 2.
Informed consent of the donor and their family, including for use of organs for research, was obtained by the local organ procurement agency prior to organ retrieval.
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