Glucose-induced beta cell dysfunction in vivo in rats: Link between oxidative stress and endoplasmic reticulum stress

C. Tang, K. Koulajian, I. Schuiki, L. Zhang, T. Desai, A. Ivovic, P. Wang, C. Robson-Doucette, M. B. Wheeler, B. Minassian, A. Volchuk, A. Giacca

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis Endoplasmic reticulum (ER) stress has been implicated in glucose-induced beta cell dysfunction. However, its causal role has not been established in vivo. Our objective was to determine the causal role of ER stress and its link to oxidative stress in glucose-induced beta cell dysfunction in vivo. Methods Healthy Wistar rats were infused i.v. with glucose for 48 h to achieve 20 mmol/l hyperglycaemia with or without the co-infusion of the superoxide dismutase mimetic tempol (TPO), or the chemical chaperones 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid (TUDCA). This was followed by assessment of beta cell function and measurement of ER stress markers and superoxide in islets. Results Glucose infusion for 48 h increased mitochondrial superoxide and ER stress markers and impaired beta cell function. Co-infusion of TPO, which we previously found to reduce mitochondrial superoxide and prevent glucoseinduced beta cell dysfunction, reduced ER stress markers. Similar to findings with TPO, co-infusion of PBA, which decreases mitochondrial superoxide, prevented glucoseinduced beta cell dysfunction in isolated islets. TUDCA was also effective. Also similar to findings with TPO, PBA prevented beta cell dysfunction during hyperglycaemic clamps in vivo and after hyperglycaemia (15 mmol/l) for 96 h. Conclusions/interpretation Here, we causally implicate ER stress in hyperglycaemia-induced beta cell dysfunction in vivo. We show that: (1) there is a positive feedback cycle between oxidative stress and ER stress in glucose-induced beta cell dysfunction, which involves mitochondrial superoxide; and (2) this cycle can be interrupted by superoxide dismutase mimetics as well as chemical chaperones, which are of potential interest to preserve beta cell function in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)1366-1379
Number of pages14
JournalDiabetologia
Volume55
Issue number5
DOIs
StatePublished - May 1 2012

Fingerprint

Endoplasmic Reticulum Stress
Oxidative Stress
Glucose
Superoxides
Phenylbutyrates
Hyperglycemia
Superoxide Dismutase
Type 2 Diabetes Mellitus
Wistar Rats

Keywords

  • Beta cell dysfunction
  • Endoplasmic reticulum stress
  • Glucotoxicity
  • In vivo
  • Oxidative stress

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Tang, C., Koulajian, K., Schuiki, I., Zhang, L., Desai, T., Ivovic, A., ... Giacca, A. (2012). Glucose-induced beta cell dysfunction in vivo in rats: Link between oxidative stress and endoplasmic reticulum stress. Diabetologia, 55(5), 1366-1379. https://doi.org/10.1007/s00125-012-2474-8

Glucose-induced beta cell dysfunction in vivo in rats : Link between oxidative stress and endoplasmic reticulum stress. / Tang, C.; Koulajian, K.; Schuiki, I.; Zhang, L.; Desai, T.; Ivovic, A.; Wang, P.; Robson-Doucette, C.; Wheeler, M. B.; Minassian, B.; Volchuk, A.; Giacca, A.

In: Diabetologia, Vol. 55, No. 5, 01.05.2012, p. 1366-1379.

Research output: Contribution to journalArticle

Tang, C, Koulajian, K, Schuiki, I, Zhang, L, Desai, T, Ivovic, A, Wang, P, Robson-Doucette, C, Wheeler, MB, Minassian, B, Volchuk, A & Giacca, A 2012, 'Glucose-induced beta cell dysfunction in vivo in rats: Link between oxidative stress and endoplasmic reticulum stress', Diabetologia, vol. 55, no. 5, pp. 1366-1379. https://doi.org/10.1007/s00125-012-2474-8
Tang, C. ; Koulajian, K. ; Schuiki, I. ; Zhang, L. ; Desai, T. ; Ivovic, A. ; Wang, P. ; Robson-Doucette, C. ; Wheeler, M. B. ; Minassian, B. ; Volchuk, A. ; Giacca, A. / Glucose-induced beta cell dysfunction in vivo in rats : Link between oxidative stress and endoplasmic reticulum stress. In: Diabetologia. 2012 ; Vol. 55, No. 5. pp. 1366-1379.
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AU - Zhang, L.

AU - Desai, T.

AU - Ivovic, A.

AU - Wang, P.

AU - Robson-Doucette, C.

AU - Wheeler, M. B.

AU - Minassian, B.

AU - Volchuk, A.

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