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- Title
SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity.
- Authors
Xin Tong; Tatsuyoshi Kono; Anderson-Baucum, Emily K.; Wataru Yamamoto; Patrick Gilon; Djamel Lebeche; Day, Richard N.; Shull, Gary E.; Evans-Molina, Carmella; Tong, Xin; Kono, Tatsuyoshi; Yamamoto, Wataru; Gilon, Patrick; Lebeche, Djamel
- Abstract
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.
- Subjects
ENDOPLASMIC reticulum; TYPE 2 diabetes; B cells; OBESITY; ANIMAL models in research; HOMEOSTASIS; CALCIUM metabolism; ANIMAL experimentation; ANIMALS; BLOOD sugar; CARRIER proteins; CELL physiology; CYTOPLASM; DIET; INSULIN; INSULIN resistance; ISLANDS of Langerhans; MICE; RESEARCH funding; PHYSIOLOGY
- Publication
Diabetes, 2016, Vol 65, Issue 10, p3039
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-0084