SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity.
(2016) Diabetes — Vol. 65, n° 10, p. 3039-3052 (2016)
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- The sarcoendoplasmic reticulum (ER) Ca(2+) ATPase 2 (SERCA2) pump is a P-type ATPase tasked with the maintenance of ER Ca(2+) 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 Ca(2+) mobilization, and the onset of steady-state glucose-induced Ca(2+) 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 Ca(2+) storage and rescued tunicamycin-induced β-cell death. In aggregate, these data suggest a critical role for SERCA2 and the regulation of ER Ca(2+) homeostasis in the β-cell compensatory response to diet-induced obesity.
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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 (Original work published 2016)