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Jan 22, 2010

Researchers Find Mechanism for Cellular Dysfunction and Apoptosis in Type 2 Diabetes

  • Islet amyloid polypeptide (IAPP) oligomers may contribute to the onset of type 2 diabetes mellitus, report scientists from the University of California, Los Angeles. They discovered that small clusters of IAPP formed within beta cells and disrupted the membranes required for insulin secretion.

    These oligomers were also found in beta cells in human patients with type 2 diabetes. Additionally, IAPP oligomers disrupted mitochondrial membranes, which can result in beta-cell death.

    There is increasing evidence that the toxic form of amyloidogenic proteins is not amyloid but smaller membrane-permeant oligomers, according to the UCLA team. They thus sought to establish the abundance and sites of formation of IAPP toxic oligomers. The investigators used an antibody specific for toxic oligomers and cryo-immunogold labeling in human IAPP transgenic mice, human insulinoma, and pancreas from humans with and without type 2 diabetes.

    Their results appear in in the February issue of The American Journal of Pathology in a paper titled “Evidence for Proteotoxicity in Beta-Cells in Type 2 Diabetes, Toxic Islet Amyloid Polypeptide Oligomers form Intracellularly in the Secretory Pathway.”

    The researchers found that IAPP toxic oligomers are formed intracellularly within the secretory pathway in type 2 diabetes. Most striking, they report, is that IAPP toxic oligomers appear to disrupt membranes of the secretory pathway. When adjacent to mitochondria, they were also seen to disrupt mitochondrial membranes.

    The authors suggest that IAPP toxic oligomers form within the secretory pathway in beta cells to an increased extent in type 2 diabetes and as a function of obesity. In light of their new research along with the known properties of toxic IAPP oligomers to induce membrane damage, they conclude that toxic oligomers may contribute to the beta-cell dysfunction and apoptosis characteristic of type 2 diabetes. 

    In patients with type 2 diabetes, insulin-secreting beta cells are progressively lost, and this loss is often associated with the accumulation of misfolded proteins, in particular IAPP. Similar amyloid protein accumulation has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease.

     



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