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GENETICS Gene Players May Tip Balance to DiabetesSlowdown of Mitochondria Could Start Slide Toward Type 2 Disease As the Star Wars saga goes, a blood sample from 10-year-old Anakin Skywalker (the young Darth Vader) tested for a Jedi record of 20,000 mitochondria per cell, even higher than the count for Yoda. Mitochondria (stage-named "midi-chlorians") were essential for human existence, symbolized the interdependence of living beings, and channeled the Force for good or bad.
Similar findings from two research groups underscore news about a mitochondrial pathway involved in type 2 diabetes. In a project based at Joslin Diabetes Center (above, from left), Atul Butte, Sarah Crunkhorn, Mary Elizabeth Patti, and colleagues found a potential genetic susceptibility in Mexican American men and women with insulin resistance and type 2 diabetes. (Below, from left) Joel Hirschhorn, David Altshuler, Vamsi Mootha (sitting), Todd Golub, Pablo Tamayo (sitting) at HMS and the Whitehead, and colleagues found a similar genetic susceptibility in Caucasian Swedish men with glucose intolerance and type 2 diabetes. (Photos by Steve Gilbert)
Now this prescient bit of popular culture is playing out with real meaning in science. Hundreds of mitochondria occupy every cell and play an increasingly prominent role in type 2 diabetes research, especially in muscle. The number and activity of mitochondria per muscle cell rise with exercise and fall in diabetes by unknown mechanisms. New research from two HMS teams has found a group of genes associated with the metabolic dark side of mitochondria in people who have or are at risk for diabetes. It appears that the genes slack off in unison to slow down the final mitochondrial steps of combining the air we breath with the food we eat or the fat we store. The oxidative phosphorylation pathway in the lethargic mitochondria may tip the scales to insulin resistance, the first metabolic defect on the road to diabetes. "There's an interesting convergence of a lot of different lines of investigation focusing on mitochondria," said David Altshuler, HMS assistant professor of genetics and of medicine at Massachusetts General Hospital. "In some ways, it's not surprising, because the mitochondria are a critical component of energy metabolism." The Gene TeamThe latest pair of studies documents how small changes in a large group of coordinated genes may contribute to diabetes risk. The researchers measured gene expression patterns of muscle biopsies from people at risk for or suffering from type 2 diabetes and healthy controls. Using different statistical methods, they identified key transcription factors that may help orchestrate the progression from insulin resistance to glucose intolerance to full-fledged disease.
"No individual genes had significantly different expression between the diabetics and matched controls," Mootha said, "so our idea was to look at predefined groups of genes, known to travel together in biological pathways, and see if we can detect subtle but consistent differences." The method provides enough statistical power to overcome the wide variation among individual genes and people. The researchers mined genomics databases to find 150 gene groups representing potential biological pathways and controls. Then they ran the numbers and discovered center stage belongs to a subset of tightly coordinated genes. In a muscle cell line, they confirmed the genes responded together to a specific transcription co-activator, peroxisome proliferator-activated receptor gamma co-activator 1alpha, known as PGC-1alpha and encoded by PPARGC1, which also showed 20 percent lower expression in the diabetic muscle tissue. (PGC-1 was discovered by co-author Bruce Spiegelman, see story above.) Affirming FindingsMeanwhile, at Joslin Diabetes Center, Mary-Elizabeth Patti, HMS assistant professor of medicine, and her colleagues reported similar results in Mexican-American men and women in the July 8 Proceedings of the National Academy of Sciences (online June 27). They used annotated gene databases to identify biologically relevant groups from the top-ranking microarray results to identify a coordinated pattern of reduction in mitochondrial oxidative metabolic genes. The genes are selectively turned on by the transcription factor dubbed nuclear respiratory factor-1 (NRF-1). That led to NRF-1 co-activators PGC-1alpha and PGC-1beta, whose expressions were nearly doubled in men with insulin resistance and a family history of diabetes in follow-up measurements."Genetics may determine how susceptible you are when things go bad," Patti said. "You may inherit a tendency to downregulate your mitochondria when you accumulate fat, a predisposition that makes things worse for you than someone else who is overweight and insulin resistant who never gets diabetes." Differences between the studies seem to strengthen the case for their similar findings--they involve different populations, ages, diabetes risk profiles, statistical methods, biopsy collection protocols, and stage of metabolic dysfunction. The results only show correlation, not cause and effect, but another recent finding lends credence to the model. In the May 16 Science, a study from Gerald Shulman's lab at Yale University School of Medicine found an age-associated decline in mitochondrial function that may contribute to insulin resistance in the elderly and may help explain the high prevalence of type 2 diabetes in this age group. Patti and Altshuler "make a compelling case, but sorting cause from consequence is hard," said Alan Attie, professor of biochemistry at the University of Wisconsin, Madison, who co-authored an accompanying commentary in the July Nature Genetics. "It's important work. It will very much be in the consciousness of everyone looking at these issues." --Carol Cruzan Morton |
