Tong, XinKono, TatsuyoshiAnderson-Baucum, Emily K.Yamamoto, WataruGilon, PatrickLebeche, DjamelDay, Richard N.Shull, Gary E.Evans-Molina, Carmella2018-03-202018-03-202016-10Tong, X., Kono, T., Anderson-Baucum, E. K., Yamamoto, W., Gilon, P., Lebeche, D., … 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/db16-00840012-1797https://hdl.handle.net/1805/15661The 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 HFD-fed S2HET islets. Moreover, HFD-fed S2HET mice 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.en-USPublisher PolicySERCA2β-cellobesityglucose homeostasisPancreasArticle