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Research implicates protein in type-2 diabetes

Aliciaby Alicia Di Rado

Sure, cells in the pancreas produce insulin-but diabetes investigators from the Keck School of Medicine of USC are hunting down the role that a second, less-familiar substance secreted by these same cells plays in type-2 diabetes.

Besides producing insulin, beta cells in the pancreas secrete a protein called human islet amyloid polypeptide, or IAPP.

In healthy people, this protein is released along with insulin into the blood, where it is thought to work as a hormone that helps regulate blood sugar. When it is released in people with type-2 diabetes, though, the protein starts to form thread-like chains, becoming an abnormal, insoluble deposit known as amyloid.

At the same time, beta cells begin to self-destruct through a process known as apoptosis, according to research presented at the American Diabetes Association’s 61st Annual Scientific Sessions in June.

Scientists have long known that as many as 90 percent of type-2 diabetes patients are found to have plaques made up of stringy protein-amyloid deposits-in the pancreas after death. So, it makes sense that IAPP might play a part in killing off beta cells.

“IAPP appears only to be harmful when it forms abnormal aggregates, leading to beta cell death,” said Peter Butler, USC professor of medicine and chief of the division of endocrinology, who set up the most recent studies to confirm that observation.

Butler noted that people with type-2 diabetes have a reduced number of beta cells, even though scientists recently found that beta cells can regenerate. Why doesn’t the pancreas replace lost beta cells in those with type-2 diabetes?

“We wanted to see if the cells that are trying to divide and repair the lost beta cells are, themselves, particularly vulnerable to cell death from IAPP aggregates, as we suspected,” Butler explained. “If this is the case, it would explain why the beta cell population remains low.”

Butler and colleagues set out to determine how forms of IAPP are toxic to cells (for example, if cell death happens through apoptosis, a sort of cellular suicide), how quickly cell death occurs and which cells are most vulnerable.

They put living cells in a solution of abnormal IAPP aggregates and observed that cells began to die six to 12 hours later. The researchers found that the IAPP aggregates were most toxic to actively replicating cells, as suspected; and of the cells that died, about 90 percent perished through apoptosis.

Yet, normal human beta cells produce IAPP. Why doesn’t IAPP kill beta cells in healthy people free from type-2 diabetes?

Butler theorizes that beta cells in healthy people are able to channel IAPP through the cell without it forming the toxic form of the protein.

People vulnerable to type-2 diabetes, Butler said, may have a genetically decreased capacity to traffic IAPP. That poses no problem if they only produce small amounts of the protein, as is true in athletic and lean people. However, with increasing weight and sedentary lifestyle-well known risk factors for type-2 diabetes-the amount of IAPP from each beta cell increases dramatically.

Butler believes that it is under these conditions that cells begin to accumulate abnormal ag-gregates of IAPP, which in turn lead to beta cell destruction, in people genetically vulnerable to type-2 diabetes.

In a second study, Butler and colleagues showed that IAPP aggregates also seem to disrupt the integrity of groups of islet cells. (Islets of Langerhans are clusters of beta cells and other cells found in the pancreas.)

Researchers used a novel technique to produce a video image of living islets. They applied IAPP aggregates to the islets, then watched what happened.

Through the time-lapse video, researchers saw that applying IAPP caused the human islets to grow larger, like a swelling sponge. At the same time, clustered cells became less attached to each other, and cells on the surface of the cluster began to detach themselves.

Researchers propose that the small IAPP chains can hurt the islets by disrupting their integrity. The mechanism is consistent with previous studies indicating IAPP aggregates disrupt membranes.

Such research may help medical scientists who are venturing into the world of islet cell transplantation. Some physicians have transplanted islets from healthy donor pancreases into the liver of patients with type-1 diabetes, so that the new donor cells begin to produce insulin. But in addition to the challenges of rejection faced in organ transplant operations, such patients face another problem: the body’s immune system may continue to attack the transplanted islet cells the same way it destroyed the original islet cells.

“This newly found mechanism of islet disruption may contribute to human islet vulnerability after islet transplantation,” Butler noted. “The more we know about how islets fail, the more successful we may be in keeping them functioning.”

Researchers in the apoptosis study included Robert A. Ritzel and Chand Sultana. Authors of the second study included Ritzel, Marianna Torok and Ralf Langen.