Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes.
The relentless decline in beta-cell function frequently observed in type 2 diabetic patients, despite optimal drug management, has variously been attributed to glucose toxicity and lipotoxicity. The former theory posits hyperglycemia, an outcome of the disease, as a secondary force that further damages beta-cells. The latter theory suggests that the often-associated defect of hyperlipidemia is a primary cause of beta-cell dysfunction. We review evidence that patients with type 2 diabetes continually undergo oxidative stress, that elevated glucose concentrations increase levels of reactive oxygen species in beta-cells, that islets have intrinsically low antioxidant enzyme defenses, that antioxidant drugs and overexpression of antioxidant enzymes protect beta-cells from glucose toxicity, and that lipotoxicity, to the extent it can be attributable to hyperlipidemia, occurs only in the context of preexisting hyperglycemia, whereas glucose toxicity can occur in the absence of hyperlipidemia.
Robertson
R Paul
RP
Pacific Northwest Research Institute and the Departments of Medicine and Pharmacology, University of Washington, Seattle, Washington 98122, USA. rpr@u.washington.edu
Harmon
Jamie
J
Tran
Phuong Oanh T
PO
Poitout
Vincent
V
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007515:Islets of Langerhans / Q000473:pathology*; D008054:Lipid Peroxides / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats
D008054:Lipid Peroxides