SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity

Xin Tong, Tatsuyoshi Kono, Emily K. Anderson-Baucum, Wataru Yamamoto, Patrick Gilon, Djamel Lebeche, Richard N. Day, Gary E. Shull, Carmella Evans-Molina

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3039-3052
Number of pages14
JournalDiabetes
Volume65
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Tong, X., Kono, T., Anderson-Baucum, E. K., Yamamoto, W., Gilon, P., Lebeche, D., Day, R. N., Shull, G. E., & Evans-Molina, C. (2016). SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity. Diabetes, 65(10), 3039-3052. https://doi.org/10.2337/db16-0084