Diabetes, glucose toxicity, and oxidative stress: A case of double jeopardy for the pancreatic islet beta cell.
Diabetes is commonly referred to in terms of type 1 and type 2. Both forms involve pancreatic islet beta-cell abnormalities, characterized by death in type 1 and accelerated apoptosis in type 2. The resultant chronic hyperglycemia leads to chronic oxidative stress for all tissues because glucose in abnormally high concentrations forms reactive oxygen species. It has been repeatedly emphasized that this can lead to oxidative damage in the classical secondary targets of diabetes, such as eyes, kidneys, nerves, and blood vessels. However, it has been much less appreciated that the beta cell itself is also a prime target, a case of double jeopardy. This situation is all the more pernicious because islets contain among the lowest levels of antioxidant enzyme activities compared to other tissues. This adverse effect of high glucose concentrations is referred to as glucose toxicity. A major manifestation of glucose toxicity in the beta cell is defective insulin gene expression, diminished insulin content, and defective insulin secretion. The molecular mechanisms involve the development of decreased levels of two very important insulin promoter transcription factors, PDX-1 and MafA. Studies with animal models of type 2 diabetes have established that pharmacologic protection against oxidative stress ameliorates the severity of diabetes progression. Translational research with humans is now under way to ascertain whether this protection can be provided to patients experiencing inadequate glycemic control.
Robertson
R Paul
RP
Department of Medicine and Department of Pharmacology, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA. rpr@pnri.org
Harmon
Jamie S
JS
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D007328:Insulin; D017382:Reactive Oxygen Species; D005947:Glucose