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

Hannah M. Gordon, Neil Majithia, Patrick E. MacDonald, Jocelyn E.Manning Fox, Poonam R. Sharma, Frances L. Byrne, Kyle L. Hoehn, Carmella Evans-Molina, Linda Langman, Kenneth L. Brayman, Craig S. Nunemaker

Research output: Contribution to journalArticle

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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. Purpose: 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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalEndocrine
DOIs
StateAccepted/In press - Apr 12 2017

Fingerprint

Prostate
Body Mass Index
Tissue Donors
Inflammation
Antigens
Type 2 Diabetes Mellitus
Obesity
Insulin
Interleukin-1
Islets of Langerhans
Leukocyte Count
Hemoglobins
Up-Regulation
Down-Regulation
Glucose
Polymerase Chain Reaction
Messenger RNA

Keywords

  • Cytokines
  • Inflammation
  • Iron
  • Islets
  • Obesity
  • Type 2 diabetes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Gordon, H. M., Majithia, N., MacDonald, P. E., Fox, J. E. M., Sharma, P. R., Byrne, F. L., ... Nunemaker, C. S. (Accepted/In press). STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. Endocrine, 1-10. https://doi.org/10.1007/s12020-017-1297-2

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

In: Endocrine, 12.04.2017, p. 1-10.

Research output: Contribution to journalArticle

Gordon, HM, Majithia, N, MacDonald, PE, Fox, JEM, Sharma, PR, Byrne, FL, Hoehn, KL, Evans-Molina, C, Langman, L, Brayman, KL & Nunemaker, CS 2017, 'STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation', Endocrine, pp. 1-10. https://doi.org/10.1007/s12020-017-1297-2
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. / STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. In: Endocrine. 2017 ; pp. 1-10.
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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. Purpose: 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.",
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T1 - STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation

AU - Gordon, Hannah M.

AU - Majithia, Neil

AU - MacDonald, Patrick E.

AU - Fox, Jocelyn E.Manning

AU - Sharma, Poonam R.

AU - Byrne, Frances L.

AU - Hoehn, Kyle L.

AU - Evans-Molina, Carmella

AU - Langman, Linda

AU - Brayman, Kenneth L.

AU - Nunemaker, Craig S.

PY - 2017/4/12

Y1 - 2017/4/12

N2 - 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. Purpose: 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.

AB - 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. Purpose: 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.

KW - Cytokines

KW - Inflammation

KW - Iron

KW - Islets

KW - Obesity

KW - Type 2 diabetes

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