Gordon Hannah M, Majithia Neil, MacDonald Patrick E, Fox Jocelyn E Manning, Sharma Poonam R, Byrne Frances L, Hoehn Kyle L, Evans-Molina Carmella, Langman Linda, Brayman Kenneth L, Nunemaker Craig S
Department of Biomedical Sciences, Ohio University, Athens, OH, USA.
Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
Endocrine. 2017 Jun;56(3):528-537. doi: 10.1007/s12020-017-1297-2. Epub 2017 Apr 12.
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.
前列腺六跨膜上皮抗原4（STEAP4）是一种金属还原酶，先前已证明其可保护细胞免受炎症损伤。STEAP4基因变异与多种与肥胖相关的代谢紊乱有关，包括2型糖尿病患者对葡萄糖急性胰岛素反应的假定缺陷。
我们研究了肥胖和/或2型糖尿病是否会改变人胰岛中STEAP4的表达。
从两个医疗中心的已故供体中分离出人胰岛，并进行定量聚合酶链反应。根据供体是否患有2型糖尿病进行分类选择。地点1（埃德蒙顿）：13名2型糖尿病供体（7名男性，6名女性），20名非糖尿病供体（7名男性，13名女性）。地点2（弗吉尼亚）：6名2型糖尿病供体（6名女性），6名非糖尿病供体（3名男性，3名女性）。
在地点1的所有供体（P<0.10）和非糖尿病供体（P<0.05）中，STEAP4的胰岛表达随体重指数增加而降低；在2型糖尿病供体中，STEAP4的胰岛表达随糖化血红蛋白升高而降低。女性供体的胰岛STEAP4表达也略高（P<0.10）。在地点2的2型糖尿病供体中，与非糖尿病供体相比，胰岛胰岛素表达降低，STEAP4表达增加，白细胞计数增加。过夜暴露于5 ng/ml白细胞介素-1β的非糖尿病供体的胰岛显示STEAP4表达增加，这与炎症信号上调STEAP4一致。
这些发现表明，STEAP4 mRNA表达增加与炎症刺激有关，而较低的STEAP4表达与人类胰岛肥胖有关。鉴于其假定的保护作用，慢性肥胖导致的STEAP4下调提示了胰岛对细胞损伤保护作用降低的一种机制。
