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Cells' Protein-Folding 'ER' May Play a Role in Type 2 Diabetes

By Jeffrey Norris

“It used to be that for a long time, we thought that type 2 diabetes was just your insulin not working — insulin resistance,” says Feroz Papa, MD, PhD. “But that’s only partly the case. Insulin resistance is just one of the problems.” Researchers are racing to learn more about the biology that drives type 2 diabetes — the type of diabetes that mostly afflicts a growing population of older and overweight people. Up to 25 million Americans now have the disease. “Type 2 diabetes has reached epidemic levels worldwide,” says Papa, a UCSF endocrinologist who treats diabetes at San Francisco General Hospital, and who also conducts lab research at the California Institute for Quantitative Biosciences (QB3). “Yet because key details of its pathogenesis are not understood, our therapeutic options remain limited.” Papa’s latest discoveries lay the groundwork for gaining a more rigorous and fundamental understanding of a type of stress that affects insulin-secreting beta cells of the pancreas. This stress may play a role in diabetes. In a study published online in the journal Cell on Nov. 20, 2008, Papa reports on experiments in which he used new tools to understand the stressed state more quantitatively in living cells. This new knowledge, in turn, could perhaps be used to identify new molecules as targets for the development of what may prove to be totally new types of drugs to fight diabetes. Beta Cells Die Beta cells of the pancreas are exquisite sensors of glucose in the blood. The beta cells know when to secrete insulin after a meal or snack. Insulin acts on cells throughout the body. The hormone allows glucose to enter the cells. The cells use the chemical energy contained within the sugar. As cells become resistant to insulin, less glucose enters the cells, and more remains in the blood. Over time, a failure to control this high blood sugar in diabetes can lead to heart attacks, kidney failure and other life-threatening complications. In recent years, it has become clear that for diabetes to occur, insulin resistance is not sufficient. In addition, as the disease develops, the insulin-secreting beta cells start dying off, Papa says. “There is a prediabetic condition where you can be insulin-resistant as all get-out. But until your beta cells fail, you do not become diabetic.” Initially, Papa explains, beta cells compensate for the body’s resistance to insulin. They make and secrete more. They get bigger and fatter, and become filled with the cellular machinery that makes insulin. “You end up with a lot of insulin floating around in your body, and this partially and temporarily overcomes the blockage of insulin signaling that’s caused by obesity and overweight,” Papa says. But under the constant stress of having to crank out insulin, the beta cells eventually burn out and die, researchers have discovered. Some drugs commonly used to treat type 2 diabetes spur surviving beta cells to crank out yet more insulin, driving cells to burn out, Papa says. Other drugs cause cells throughout the body to become more sensitive to the hormone, and these drugs can partially retard progression of the prediabetic state. But there are no good ways yet to actually modify the disease process of beta cell death, so the disease continues its slow but steady progression. Papa is learning more about how the insulin-making cells die, with the goal of finding ways to keep these beta cells alive and productive. He thinks beta cell death in type 2 diabetes may occur when the cells’ protein-folding factories become overtaxed from having to prepare so much insulin for export. ER Stress and Beta Cell Death All cells make proteins, but not always perfectly. Some individual protein molecules do not always fold correctly into their normal shapes. A compartment within cells called the endoplasmic reticulum, or ER for short, acts as a protein-folding factory for secreted proteins such as insulin. Papa hypothesizes that unrelenting insulin production can overtax the ER, leading to the condition of “ER stress.” This triggers a chain of events that leads the beta cells to commit suicide if the ER stress cannot be resolved. Sorting out stress and responses to stress in the ER has been a bit like trying to figure out what’s going on inside a sealed black box. But in the current online edition of Cell, Papa reports a breakthrough that enables him to do just that. The approach may allow Papa and other researchers to crack the mysteries of the ER, which could eventually aid understanding of how beta cells die in diabetes. More practically, the tools should be useful to sort and select therapies that prolong the lives of cells without causing the cells to become stressed. In 2007, Papa received a National Institutes of Health Director’s New Innovator Award to advance this research. He was one of just 29 recipients out of more than 2,100 applicants.


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