Sci. Aging Knowl. Environ., 23 March 2005
Diabetes-linked mutations cripple gene-control protein in pancreas cells
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/12/nf22
The pancreas manages the body's rapid response to sugar. Now, researchers have identified a protein that apparently helps the organ fire up when sugar loads rise. Some diabetics have faults in the molecule, and the snags hinder the protein's ability to activate the insulin gene. But experts caution that further work is required to definitively link the molecule to diabetes.
In type II diabetes, blood sugar concentrations swing out of control because body tissues don't respond to the sugar-controlling hormone insulin. To compensate, the pancreas pumps out even more insulin, stressing itself and eventually causing a shutdown. Several years ago, geneticist Philippe Froguel of Imperial College, London, and colleagues identified a chromosomal region linked to diabetes. The segment contains a protein called KLF11 that previous studies had suggested might help protect against pancreatic cancer. The protein, which controls the activity of a variety of genes, resides in so-called exocrine cells of the pancreas, which produce and dispense digestive fluids. Froguel and his team wondered whether the molecule also loiters in the pancreas's cells, which produce insulin, and helps control blood sugar.
First, the team tested cells from cultured lines and from human pancreases and discovered that both kinds contained KLF11. Moreover, the cells spun more of the protein when bathed in glucose. Sugar treatment also prompted KLF11 to grab the gene that encodes insulin and turn it on. Those findings suggested that KLF11 helps cells respond to a changing sugar burden and that glitches in KLF11 could hasten diabetes.
To address the KFL11-diabetes connection, the team scrutinized families with an inherited susceptibility to the disease. Three families carried two different hiccups in KLF11 that did not appear in nondiabetic individuals. The team then analyzed nearly 1500 people with type II diabetes from the general population. Several genetic alterations in KLF11 showed up more frequently in diabetics than in healthy controls.
Next, the researchers discerned how KLF11 glitches alter cell operation. Cells expressing one of the variants produced half as much insulin in response to a glucose infusion than did cells with normal KLF11. In addition, nondiabetic people carrying a diabetes-linked version of KLF11 produced less insulin in response to a glucose injection, and they couldn't lower blood glucose quantities as quickly as could individuals with the normal form of the gene.
Developmental biologist Jan Jensen of the University of Colorado Health Sciences Center in Denver praises the work for "complementing the genetics with functional studies of the gene." However, he notes that KLF11 could influence diabetes susceptibility through other tissues, such as fat or muscle, rather than through cells. Molecular endocrinologist Melissa Thomas of Harvard University says, "it's a very exciting paper," but researchers must replicate the findings in other populations to determine "how big a contributor KLF11 is." KLF11 controls antioxidant genes important for protecting cells, she says. Perhaps that activity, rather than direct action on the insulin gene, is responsible for KLF11's connection to diabetes. The work should inspire researchers to take a closer look at KLF11's role in responding to sugar emergencies.
March 23, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150