Study Uncovers Potential New Ways to Prevent Beta Cell Death in Type 2 Diabetes

Andrew Miranker and Diana Schlamadinger
Andrew Miranker, PhD, with postdoctoral fellow Diana Schlamadinge, PhD

Generally, proteins freely move within a cell to perform their various functions. However, some proteins, known as amyloid proteins, have the tendency to stick to one another. These proteins first form fibers that then aggregate in large networks called amyloid deposits. The aggregated amyloid proteins are not functional, and instead are often harmful. In both Alzheimer's and diabetes, amyloid deposits are believed to play a central role in the cellular damage and cell death that leads to disease. For example, amyloid beta (A beta) deposits are a defining feature in the brain of people affected by Alzheimer's disease. Islet amyloid polypeptide (IAPP), a molecule that is normally secreted alongside insulin, forms amyloid deposits that are found in the pancreatic beta cells of nearly all people with type 2 diabetes, and have also been implicated in the failure of islet transplants in people with type 1 diabetes.

It is not known what normally prevents amyloid deposit formation, or how the formation of amyloid deposits is triggered in disease. With support from the American Diabetes Association, Dr. Andrew Miranker, a biochemist and biophysicist at Yale University, has been studying what triggers amyloid aggregation and how the deposits lead to beta cell death in the pancreas. The goal of his project is to find ways to prevent beta cell damage that leads to type 2 diabetes.

Dr. Miranker and his postdoctoral fellow Diana E. Schlamadinger, PhD, developed a controlled laboratory system to study the formation of amyloid deposits. Using this system, they showed that components of natural membranes isolated from beta cells inhibit the formation of amyloid fibers, suggesting that beta cell membranes normally inhibit the formation of amyloid fibers in healthy people.

They also discovered, surprisingly, that when pre-formed amyloid fibers were added to beta cells, they didn't damage them. This finding suggested that the amyloid fibers alone were not sufficient to be toxic to the cells. However, when pre-formed IAPP fibers were combined with fresh IAPP proteins, together they formed a toxic amyloid precursor. These disrupted the membranes and led to beta cell damage and death. This is a new clue about how fibers could be a trigger required for the development of amyloid and how fibers might be responsible for loss of beta cells. Similar findings have been reported for A beta peptide in Alzheimer's disease, so this may be a common characteristic of different types of amyloid proteins as they form deposits.

With a better understanding of how amyloid toxicity develops, Drs. Miranker and Schlamadinger next wanted to see whether they could disrupt this process. Using information about the atomic structure of IAPP, they were able to develop a series of small molecules that have the unique ability to bind membrane associated IAPP. They identified several compounds that were effective in preventing fiber formation in the presence of cell membranes. Importantly, these compounds also prevented beta cell death. The investigators are now using these inhibitor molecules to understand how IAPP associates with cell membranes and how to most effectively disrupt the aggregation process to protect beta cells. Their findings could inform the development of new drugs to preserve beta cell function in people at risk for diabetes, and may also inform similar therapeutic approaches for other amyloid-associated diseases such as Alzheimer's disease.

  • Last Reviewed: August 7, 2015
  • Last Edited: August 10, 2015

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