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 Day, Gary E. Shull, Carmella Evans-Molina

Research output: Contribution to journalArticle

20 Citations (Scopus)

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

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Reticulum
Calcium-Transporting ATPases
High Fat Diet
Obesity
Diet
Glucose
Homeostasis
Insulin
Proinsulin
Tunicamycin
Obese Mice
Adiposity
Adenosine Triphosphatases
Insulin Resistance
Cell Death
Fats
Maintenance
Cell Proliferation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity. / Tong, Xin; Kono, Tatsuyoshi; Anderson-Baucum, Emily K.; Yamamoto, Wataru; Gilon, Patrick; Lebeche, Djamel; Day, Richard; Shull, Gary E.; Evans-Molina, Carmella.

In: Diabetes, Vol. 65, No. 10, 01.10.2016, p. 3039-3052.

Research output: Contribution to journalArticle

Tong, X, Kono, T, Anderson-Baucum, EK, Yamamoto, W, Gilon, P, Lebeche, D, Day, R, Shull, GE & Evans-Molina, C 2016, 'SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity', Diabetes, vol. 65, no. 10, pp. 3039-3052. https://doi.org/10.2337/db16-0084
Tong X, Kono T, Anderson-Baucum EK, Yamamoto W, Gilon P, Lebeche D et al. SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity. Diabetes. 2016 Oct 1;65(10):3039-3052. https://doi.org/10.2337/db16-0084
Tong, Xin ; Kono, Tatsuyoshi ; Anderson-Baucum, Emily K. ; Yamamoto, Wataru ; Gilon, Patrick ; Lebeche, Djamel ; Day, Richard ; Shull, Gary E. ; Evans-Molina, Carmella. / SERCA2 deficiency impairs pancreatic β-cell function in response to diet-induced obesity. In: Diabetes. 2016 ; Vol. 65, No. 10. pp. 3039-3052.
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