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A newly discovered gene for type 2 diabetes has been identified with thehelp of gene-chip technology, researchers recentlyannounced.
In studies of mice, the absence of the aryl hydrocarbon receptor nucleartranslocator gene, called ARNT, resulted in the development of hyperglycemiaand diabetic symptoms. Mice who had the gene did not develop these symptoms.Researchers plan to further investigate the role of the ARNT gene in type 2diabetes in humans.
Gene-chip research is "opening up new diagnostic avenues for diabetesand potentially new therapeutic targets," says C. Ronald Kahn, MD,president and director of the Joslin Diabetes Center in Boston and professorat Harvard Medical School, also in Boston.
Kahn presented the genomic findings at the 15th Annual Meeting and ClinicalCongress of the American Association of Clinical Endocrinologists (AACE), heldApril 26–30 in Chicago.
"Over the last 10 years we have made a real quantum leap in ourability to study insulin action and disease-related processes," saysKahn, whose work has involved using genetically engineered mice withknockedout insulin receptors in target tissues such as liver, muscle, and fatto reveal important links between obesity, diabetes, and other disorders.
During his AACE presentation, Kahn focused on his work with colleagues onthe Diabetes Genome Anatomy Project (DGAP), a consortium of institutionsinvolved in the use of DNA chips and proteomic techniques to study geneticfactors in the cause of type 2 diabetes, obesity, and other insulin-resistantstates. Gene-chip technology uses a half-inch chip in a handheld device thatidentifies RNA matches. RNA controls gene expression and, in this case, DGAPresearchers are probing genes' expression in the insulin signaling network.DGAP is an initiative of the National Institute of Diabetes and Digestive andKidney Diseases.
The goal of DGAP is to better understand the relationship between genes andinsulin action, insulin resistance, and the genetics of type 2 diabetes. Studyresults will help build a database of the genes expressed in tissues regulatedby insulin, insulin resistance, and diabetes and help investigators assesslevels and patterns of gene expression in those tissues before and afterinsulin stimulation.
In addition, DGAP aims to link gene expression at the protein level withthe genetic and metabolic phenotype of the animal or cell. Finally, theproject intends to use genomic information from a panel of humans with type 2diabetes to focus on the genes that are most highly regulated by insulin anddiabetes. This will allow researchers to determine the variation in thesegenes and the proteins they encode, which might influence one's risk ofdiabetes or insulin resistance.
Kahn says four main areas of focus for DGAP are:
DGAP researchers identified the ARNT gene while investigating three thingsknown to control beta-cell dysfunction—transcription factors, glucoseuptake and metabolism, and insulin-signaling genes.
ARNT is among the critical transcription factors for normal embryonicdevelopment and plays a role in the body's response to hypoxic conditions andenvironmental elements such as dioxin. These transcription factors alsoregulate the expression and activity of other genes in a cell, therebysignificantly influencing cell function.
"This breathtaking basic science should permit us a betterunderstanding of the development of diabetes and hopefully allow newtherapeutic tools to manage diabetes more effectively," says Victor L.Roberts, MD, professor of medicine at the University of Florida in Gainesvilleand a member of the national board of directors of AACE.
In an August 2005 paper published in Cell, the Joslin researchersfound that reducing ARNT levels in beta-cells in culture produced markedlyimpaired glucose-stimulated insulin release and changes in islet geneexpression similar to those in humans with type 2diabetes.1 Inaddition, beta-cell–specific ARNT knockout mice showed abnormal glucosetolerance, impaired insulin secretion, and changes in islet gene expressionlike those in human diabetic islets.
"Together, these data suggest an important role for decreased ARNTand altered gene expression in the impaired islet function of human type 2diabetes," the researchers conclude. 
Footnotes
More information about the Diabetes Genome Anatomy Project is available atwww.diabetesgenome.org.
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