STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation

Abstract

Six-transmembrane epithelial antigen of the prostate 4 (STEAP4) 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 (T2D). Purpose We examined whether obesity and/or T2D altered STEAP4 expression in human pancreatic islets. Methods Human islets were isolated from deceased donors at two medical centers and processed for quantitative PCR. Organ donors were selected by status as non-diabetic or having T2D. Site1 (Edmonton): N=13 T2D donors (7M, 6F), N=20 non-diabetic donors (7M, 13F). Site2 (Virginia): N=6 T2D donors (6F), N=6 non-diabetic donors (3M, 3F). Results STEAP4 showed reduced islet expression with increasing BMI among all donors (P<0.10) and non-diabetic donors (P<0.05) from Site1; STEAP4 showed reduced islet expression among T2D donors with increasing HbA1c. Islet STEAP4 expression was also marginally higher in female donors (p<0.10). Among T2D donors from Site2, 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 5ng/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 known protective role, downregulation of STEAP4 by chronic obesity suggests a mechanism for reduced islet protection against cellular damage.

STEAP4: its emerging role in metabolism and homeostasis of cellular iron and copper

“…In human islets, STEAP4 expression is reduced in obesity and hyperglycemia (HbA1c), but elevated in donors with high white blood cell count (Gordon et al 2017). Islet STEAP4 expression also appears to be slightly higher in women compared to men (Gordon et al 2017). To date, little is known about the function or localization of STEAP4 in islets and warrants further study.…”

“…Further, in human pancreatic islets, reduced STEAP4 gene expression correlates with increased BMI (Gordon et al 2017) among non-diabetic donors, but not among donors with T2D. Donors with T2Dshowed reduced STEAP4 gene expression with increased HbA1c, a key indicator of chronic hyperglycemia (Gordon et al 2017). On balance, these findings suggest that reduced STEAP4 expression is associated with obesity.…”

Investigating the Expression and Function of the Glucose Transporter GLUT6 in Obesity

“…To investigate whether GLUT6 expression was also upregulated in obese and insulin-resistant human islets, we analyzed SLC2A6 mRNA levels in pancreatic islets from a cohort of human patients with and without type 2 diabetes with a body mass index (BMI) between 18 and 53. Donor information is as previously published [ 19 ] and given in Table S1 . These data showed that human islet SLC2A6 mRNA was significantly correlated with body mass index ( p = 0.005) ( Figure 1 C).…”

“…The source of the human islet samples from patients with or without type 2 diabetes used herein has been described previously [ 19 ]. Ethics approval was obtained from the University of Virginia Institutional Review Board (protocol #14904).…”

The expression of STEAP4 in peripheral blood predicts the outcome of septic patients

“…It was found to be highly expressed after the induction of TNF-α (6), and was later proven to be upregulated by other inflammatory cytokines such as IL-6 and IL-1β (7). A large number of studies have confirmed that STEAP4 is involved in the chronic inflammatory response of adipocytes during the pathogenesis of diabetes (7,8), and lower STEAP4 expression is associated with obesity and insulin resistance (9). Furthermore, some studies have shown that STEAP4 plays a protective role against inflammatory damage in hepatocytes (10), mesangial cells (11), and synovial cells (12).…”