title: SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity.
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.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Kono
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Anderson-Baucum
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.affiliation: Pôle d'endocrinologie, diabète et nutrition, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gilon
authors.affiliation: Cardiovascular Research Institute and Diabetes Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Day
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN Department of Medicine, Indiana University School of Medicine, Indianapolis, IN Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN Roudebush VA Medical Center, Indianapolis, IN cevansmo@iu.edu.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium