Sci. Aging Knowl. Environ., 17 August 2005
Lethargic pancreas gene might unleash diabetes
If the manager at a fast-food joint always knocks off early, the other employees probably won't work very hard. Similarly, a "supervisor" gene that slacks off in pancreas cells might help trigger diabetes, a new study shows. Losing the gene thwarts the activity of other genes that control how the cells respond to glucose and release insulin. The work might provide a new target for antidiabetes drugs.
Patients with type 2 diabetes lose control of their blood glucose. Excess sugar can injure the eyes, kidneys, and nerves and promote heart attacks and strokes. Researchers have identified two key failings in the disease. One, known as insulin resistance, occurs when muscles, fat, and other tissues stop heeding insulin's order to imbibe blood glucose (see "No Take Backs"). Scientists know much less about the other defect--faltering cells in the pancreas, which normally pump out insulin after a meal. Obtaining pancreas cells from patients is difficult, hindering the study of this problem. To find out how cells go awry, endocrinologist Jenny Gunton, now at the Garvin Institute in Sydney, Australia, and colleagues gathered fresh cells from cadavers whose organs were being donated.
The researchers used microarrays to compare gene activity in cells from normal and diabetic individuals. As expected, output from genes that help cells detect glucose and dispatch insulin declined steeply in diabetics. However, the identity of the gene that underwent the biggest drop-off, ARNT, was a surprise. Its protein teams with others to help cells cope with stresses such as oxygen scarcity and toxins, and no previous studies had implicated it in diabetes. Because ARNT controls many genes, its slowdown could explain the sluggishness of other -cell genes. To test that idea, the team stifled ARNT production in mouse pancreas cells. This procedure slashed the cells' insulin release. Moreover, the cells showed many of the same gene-activity changes as did cells from diabetics.
Next, the researchers engineered mice to eliminate ARNT from only the pancreas. cells from the altered rodents released less insulin than normal, and their gene-activity profiles were similar to those of cells from diabetics. The team then gauged the altered rodents' response to glucose. Sugar normally provokes an insulin surge, but it spurred no increase in female ARNT-lacking mice. Modified males did respond normally--a disparity the researchers can't explain. Overall, the work pinpoints a gene that might contribute to type 2 diabetes, says Gunton. The identification could pay off for patients, she says: "If we can increase ARNT in cells, it might make a big difference." The researchers aren't sure what slows down the gene in pancreas cells, Gunton adds, but toxins such as dioxin can affect ARNT, suggesting that pollution could be responsible.
The study reaches the same conclusion using multiple lines of evidence, says developmental biologist Jan Jensen of the University of Colorado Health Sciences Center in Aurora: "That is what I like about it." The results will stimulate further investigations of how -cell defects spur diabetes, he says. That work might uncover ways to keep ARNT on the job.
August 17, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150