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

Diabetologia. 2012 May;55(5):1366-79. doi: 10.1007/s00125-012-2474-8. Epub 2012 Mar 1.


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 glucose-induced beta cell dysfunction, reduced ER stress markers. Similar to findings with TPO, co-infusion of PBA, which decreases mitochondrial superoxide, prevented glucose-induced 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Cyclic N-Oxides / pharmacology
  • Endoplasmic Reticulum Stress / drug effects*
  • Female
  • Glucose / adverse effects*
  • Hyperglycemia / chemically induced
  • Hyperglycemia / metabolism
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Oxidative Stress / drug effects*
  • Phenylbutyrates / pharmacology
  • Rats
  • Rats, Wistar
  • Spin Labels
  • Superoxides / analysis
  • Taurochenodeoxycholic Acid / pharmacology


  • Antioxidants
  • Cyclic N-Oxides
  • Phenylbutyrates
  • Spin Labels
  • Superoxides
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • 4-phenylbutyric acid
  • Glucose
  • tempol