TY - JOUR
T1 - SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity
AU - Tong, Xin
AU - Kono, Tatsuyoshi
AU - Anderson-Baucum, Emily K.
AU - Yamamoto, Wataru
AU - Gilon, Patrick
AU - Lebeche, Djamel
AU - Day, Richard N.
AU - Shull, Gary E.
AU - Evans-Molina, Carmella
N1 - Publisher Copyright:
© 2016 by the American Diabetes Association.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - The sarcoendoplasmic reticulum (ER) Ca2+ ATPase 2 (SERCA2) pump is a P-type ATPase tasked with the maintenance of ER Ca2+ stores. Whereas β-Cell SERCA2 expression is reduced in diabetes, the role of SERCA2 in the regulation of whole-body glucose homeostasis has remained uncharacterized. To this end, SERCA2 heterozygous mice (S2HET) were challenged with a high-fat diet (HFD) containing 45% of kilocalories from fat. After 16 weeks of the HFD, S2HET mice were hyperglycemic and glucose intolerant, but adiposity and insulin sensitivity were not different between HFD-fed S2HET mice and HFD-fed wild-type controls. Consistent with a defect in β-Cell function, insulin secretion, glucose-induced cytosolic Ca2+ mobilization, and the onset of steady-state glucose-induced Ca2+ oscillations were impaired in HFDfed S2HET islets.Moreover, HFD-fed S2HETmice exhibited reduced β-Cell mass and proliferation, altered insulin production and proinsulin processing, and increased islet ER stress and death. In contrast, SERCA2 activation with a small molecule allosteric activator increased ER Ca2+ storage and rescued tunicamycin-induced β-Cell death. In aggregate, these data suggest a critical role for SERCA2 and the regulation of ER Ca2+ homeostasis in the β-Cell compensatory response to diet-induced obesity.
AB - The sarcoendoplasmic reticulum (ER) Ca2+ ATPase 2 (SERCA2) pump is a P-type ATPase tasked with the maintenance of ER Ca2+ stores. Whereas β-Cell SERCA2 expression is reduced in diabetes, the role of SERCA2 in the regulation of whole-body glucose homeostasis has remained uncharacterized. To this end, SERCA2 heterozygous mice (S2HET) were challenged with a high-fat diet (HFD) containing 45% of kilocalories from fat. After 16 weeks of the HFD, S2HET mice were hyperglycemic and glucose intolerant, but adiposity and insulin sensitivity were not different between HFD-fed S2HET mice and HFD-fed wild-type controls. Consistent with a defect in β-Cell function, insulin secretion, glucose-induced cytosolic Ca2+ mobilization, and the onset of steady-state glucose-induced Ca2+ oscillations were impaired in HFDfed S2HET islets.Moreover, HFD-fed S2HETmice exhibited reduced β-Cell mass and proliferation, altered insulin production and proinsulin processing, and increased islet ER stress and death. In contrast, SERCA2 activation with a small molecule allosteric activator increased ER Ca2+ storage and rescued tunicamycin-induced β-Cell death. In aggregate, these data suggest a critical role for SERCA2 and the regulation of ER Ca2+ homeostasis in the β-Cell compensatory response to diet-induced obesity.
UR - http://www.scopus.com/inward/record.url?scp=84989206813&partnerID=8YFLogxK
U2 - 10.2337/db16-0084
DO - 10.2337/db16-0084
M3 - Article
C2 - 27489309
AN - SCOPUS:84989206813
SN - 0012-1797
VL - 65
SP - 3039
EP - 3052
JO - Diabetes
JF - Diabetes
IS - 10
ER -