Islet amyloid: A long-recognized but underappreciated pathological feature of type 2 diabetes

  • Kahn S
  • Andrikopoulos S
  • Verchere C
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Abstract

In both type 1 and type 2 diabetes, diabetic complica- tions in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addi- tion to their ability to directly inflict damage on macro- molecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensi- tive pathways. These pathways include nuclear factor- ?B, p38 mitogen-activated protein kinase, NH2-terminal Jun kinases/stress-activated protein kinases, hex- osamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same path- ways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, acti- vation of stress pathways plays a key role in the devel- opment of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes.

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Authors

  • Steven E. Kahn

  • Sofianos Andrikopoulos

  • C. Bruce Verchere

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