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| |  Protein that Thrives in the Cells of the Obese Leads to Insulin Resistance SAN FRANCISCO, Sept. 27, 1996 -- Obesity has long been known to be a major risk factor for diabetes, but the reason why has been unclear. UCSF researchers now report in the October issue of Diabetes that obesity's contribution to the onset of diabetes may be to increase levels of a protein that hampers the ability of cells to use the hormone insulin. Many cases of the most common form of the disease, called type II diabetes, may be caused by a previously unsuspected protein called PC-1, said Ira Goldfine, M.D., director of the Division of Diabetes and Endocrine Research at UCSF/Mount Zion Medical Center and the leader of the research team. According to Goldfine, professor of medicine and physiology at UCSF, it may be possible to successfully treat diabetes in a significant percentage of cases by developing drugs that target PC-1. Type II diabetes, also called adult-onset diabetes, is a disease of sugar intolerance that affects about 15 million, mostly older and obese Americans. It accounts for 90 to 95 percent of all diabetes. In this form of the disease, the cells of the body fail to respond adequately to insulin, which is secreted by the pancreas and circulates in the blood throughout the body. In contrast, in type I diabetes, also known as juvenile-onset diabetes, the insulin-producing cells of the pancreas are destroyed by the body's immune system. "The aging of the population, the prevalence of obesity, and sedentary lifestyles are leading to a rise in the incidence of type II diabetes, much of which goes undiagnosed," Goldfine said. "Our work suggests the protein PC-1 has a role in the failure of many obese individuals to respond normally to insulin. This insulin resistance is a major risk factor in the development of diabetes. In addition, insulin resistance now also appears to be implicated in processes that independently lead to heart disease. For both reasons we think it's important to learn more about how PC-1 works." UCSF post-doctoral fellow Jack Youngren and others in Goldfine's laboratory conducted the study in collaboration with G. Lynis Dohm, Ph.D., at East Carolina University. The researchers obtained abdominal muscle tissue from 14 type II diabetic patients and 34 non-diabetic patients, all of whom underwent elective surgery for a variety of medical conditions. In both patient categories, the study included non-obese as well as obese individuals. In studies on the muscle strips, the researchers found that, independent of diabetes, excess body fat was associated with higher cellular levels of PC-1 and insulin resistance. Together with the researchers' previous findings, the new results suggest a causative role for PC-1 in insulin resistance. In earlier work, Goldfine and colleagues, including Betty Maddux, a medical specialist working in Goldfine's lab, purified PC-1 and showed that PC-1 reduced glucose uptake by cells growing in culture. The researchers demonstrated that the protein reduces glucose uptake by blocking the function of an enzyme that activates signaling inside the cell by the insulin receptor. About 70 to 80 percent of type II diabetics are obese, but genetic factors as well as obesity play a role in the insulin resistance that appears to be a leading cause of diabetes, Goldfine said. Normally, when an insulin molecule attaches to an insulin receptor on the cell surface, events are triggered inside the cell that cause the sugar called glucose to be taken in as an energy source to meet the cell's metabolic needs. However, in type II diabetes the cells fail to take up glucose adequately. This failure may be due to excess of PC-1, which prevents the receptor from working properly, Goldfine said. In diabetes, the build-up of circulating glucose that arises from food ingestion directly leads to tissue damage. The resulting complications from injury to kidneys, nerves or blood vessels may progress to blindness, severe disability or death. The contribution of diabetes to hypertension and the clogging of arteries is well established, Goldfine said. But in addition, insulin resistance itself, independent of the high glucose levels associated with diabetes, has recently come to light as a condition that can contribute to heart disease, he added. Insulin resistance is believed to lead to a heightened risk of heart disease because the pancreas tries to compensate and meet the body's metabolic needs by pumping out more insulin. The excess of insulin circulating in the bloodstream may cause heart disease by elevating levels of harmful fats called triglycerides and by increasing blood pressure, Goldfine explained. "If we develop drugs to inhibit PC-1, in many cases we may be able to combat insulin resistance in heart disease and in type II diabetes," he said.
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