|
||||||||
|
RESEARCH BRIEFS
Inflammation Marker Tied to Type 2 DiabetesEvery extra pound proportionately increases the risk of type 2 diabetes, even in the normal weight ranges. But not every overweight and obese person develops the disease. Now, researchers at HSPH and HMS have found another strong and independent predictor of diabetes, C-reactive protein (CRP), a marker of inflammation that is better known as a risk factor for cardiovascular disease.In a study published in the March issue of Diabetes, the highest levels of CRP in the blood quadrupled the chance of developing diabetes in women compared to the lowest levels, even after adjusting for body weight.
"Being able to predict a fourfold increased risk of type 2 diabetes may have major clinical implications in targeting interventions, because we're already talking about a common disease," said senior author JoAnn Manson, the Elizabeth F. Brigham professor of women's health at HMS and Brigham and Women's Hospital. "At this point, we're not saying that doctors should routinely measure CRP for the purpose of predicting type 2 diabetes. We would like to see more research, but it looks promising as a marker of risk." Although the researchers adjusted the results to eliminate the risk of extra weight and lifestyle factors, it makes sense to Manson that substances produced by fat might play a role in the disease process. "Fat tissue is often regarded as an inert storage depot," she said. "In reality, it is a highly active and dynamic organ that secretes hormones and cytokines. The mechanisms through which fat tissue causes insulin resistance in distant tissue, such as liver and skeletal muscle, is not well understood. This study really suggests that some circulating messenger produced by the fat cell induces insulin resistance and increases the risk of developing type 2 diabetes, and this may relate to increased risk of cardiovascular disease as well." Led by first author Frank Hu, HSPH associate professor of nutrition and epidemiology and HMS assistant professor of medicine at BWH, the researchers compared 737 women in the Nurses' Health Study who developed diabetes within 10 years of providing blood samples with 785 women in the study of similar age, race, and weight who did not develop diabetes. --Carol Cruzan Morton
Brake-off, Gas-on Approach Drives Nerve Cell RegrowthInjured nerve fibers have to travel a rocky road to reconnect with other neurons. Proteins in the myelin sheath that surrounds axons put out signals that essentially tell the regenerating axons not to grow. Researchers have tried blocking myelin's inhibitory influence, but this approach has produced only slight axonal growth. They have also tried to activate the nerve cells' growth program, but the strategy on its own has produced relatively little regeneration.A team of Children's Hospital researchers reports in the Feb. 18 Journal of Neuroscience that a two-pronged approach--blocking the myelin protein's inhibitory signals and activating neurons' growth program--enables injured rat optic nerves to regrow to an unprecedented degree. "Knocking out inhibitory molecules alone is not enough because the nerve cells themselves are still in a sluggish state," said Larry Benowitz, HMS associate professor of neurosurgery. "Our idea was to step on the gas--to activate the growth state at the same time." To activate the damaged nerve cells, Dietmar Fischer, HMS research fellow in surgery and first author on the paper, induced an eye injury in the rats, which drew macrophages to the site. Macrophages release growth factors that stimulate the injured optic nerves to grow. Overcoming the braking action of the myelin proteins was more complicated. Myelin-associated proteins exert their inhibitory effects on neurons through the Nogo receptor. Using a modified, noninfectious virus as a carrier, the researchers transferred a gene for a mutant (dominant-negative) Nogo receptor, developed by Zhigang He, HMS assistant professor of neurology, into retinal nerve cells. The mutant receptor sopped up the myelin-associated inhibitor proteins before they could block growth. Though the double-pronged strategy produced three times more axon regrowth than that achieved by growth factors alone, it was not enough to restore vision. "We have to fine-tune the system, and we have some ideas of how to do it. But then we come to another hurdle," Benowitz said. That hurdle is getting the nerve fibers from the eye to connect to the correct centers in the brain. "It is a mapping problem," he said. Meanwhile, he and his colleagues have begun using a similar two-pronged approach to regrow axons damaged by stroke or spinal cord injury.
Role Strengthened for Enzyme in Suppressing Breast TumorsMutations in the BRCA1 and BRCA2 genes greatly increase the risk of developing breast cancer. However, they only account for half of the familial or hereditary breast cancer cases, indicating that other gene mutations or polymorphisms must predispose women to this disease.One such candidate is the gene for BRCA1-associated C-terminal helicase, or BACH1. In 2001, researchers in the lab of David Livingston, the Emil Frei professor of medicine at HMS and the Dana-Farber Cancer Institute, discovered BACH1 through its association with the C-terminal end of BRCA1. They also uncovered mutations in the BACH1 gene in two women with early-onset breast cancer, mutations that were absent in more than 200 control volunteers. Now Livingston and colleagues report that these mutations strike at the very core of the helicase, rendering it inactive. The results, reported in the Feb. 24 Proceedings of the National Academy of Sciences, bolster the case that BACH1 may be important for suppressing breast cancer. Joint lead authors on the paper, Sharon Cantor from the University of Massachusetts Medical Center, Worcester, and Ronny Drapkin, an HMS instructor in pathology in Livingston's lab, first set out to prove that BACH1 was indeed a helicase, as its protein sequence predicted. Helicases unwind DNA, exposing the strands for copying or repair. To test if BACH1 can do this, Cantor and Drapkin overexpressed the protein, then incubated it with a circular single-stranded DNA plasmid to which a radiolabeled complementary fragment was annealed. Sure enough, BACH1 satisfied the requirements of a bona fide helicase, unwinding the labeled fragment from the plasmid in a time- and ATP-dependent manner. Next, Cantor and Drapkin tested if the two genetic changes discovered in 2001 compromise the enzyme's activity. These point mutations result in simple amino-acid substitutions, an alanine for proline at position 47 and an isoleucine for a methionine at position 299. The first mutant, it turns out, has neither helicase nor ATPase activity. The M299I mutant has slightly higher than normal ATPase activity, but failed to unwind longer duplexes (of 99 base pairs) that the wild type enzyme handled with ease. "The role of BRCA1 in DNA repair seems to be dependent on BACH1," said Drapkin, "so the fact that BACH1 is a catalytic enzyme that works on DNA fits very nicely. When you disrupt that interaction, you disrupt the kinetics of DNA repair, that's why BACH1 mutations may account for some unexplained breast cancers." But Drapkin cautions that the numbers of breast cancer patients carrying such mutations are likely to be low. --Tom Fagan |
