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Molecular Mechanism of Rare Form of Diabetes Revealed

Researchers have uncovered the molecular mechanism underlying a rare and severe form of diabetes, i.e., permanent neonatal diabetes mellitus. Children with this genetic form of diabetes have symptoms by age six months and have a lifelong dependence on insulin to maintain proper glucose levels. To investigate the disease mechanism, researchers used animal and cellular models to focus on a mutation of the KATP gene that is known to be linked to the disease. The KATP gene codes for an ATP-sensitive potassium ion channel. "The KATP channel essentially functions as a gatekeeper for insulin secretion by pancreatic beta cells,” said Dr. Faith Kline, the lead author of the study. “Without proper regulation by this gatekeeper, the pancreatic beta cells are unable to efficiently regulate insulin secretion." The researchers showed that the chaperone molecule ankyrin is present in pancreatic beta cells and that the KATP mutation prevents most KATP channels from binding with ankyrin. This failure prevents the KATP channels from reaching their normal destination in the cell membrane. "Ankyrin proteins are like cellular taxi cabs that carry passenger channels to the cell membrane. In the case of this KATP gene mutation, the ankyrin and channels cannot interact properly, and so the channels basically 'miss their ride' and do not get to the desired location," said Dr. Peter Mohler, the article’s senior author. The team also found that the few mutant KATP channels that do reach the pancreatic cell membrane do not respond to alterations in cellular metabolism. As a result, the pancreatic beta cells do not release insulin appropriately. This work was reported in the September 8 week’s early online edition of PNAS. The findings may help identify new molecular targets for treating both rare and common forms of diabetes and hyperinsulinemia.

Addiction Gene Identified in Population Group

Researchers at the Yale University School of Public Health and Princeton University have identified a gene variant that is associated with addictive behaviors in white women of European origin. Genome-wide association studies revealed that a SNP variant of the PKNOX2 gene, located on chromosome 11, is associated, in these women, with multiple (two or more) dependencies involving nicotine, alcohol, marijuana, cocaine, opiates, and other drugs. While genes on other chromosomes have previously been associated with alcoholism and drug abuse in prior studies, this is believed to be the first time that the PKNOX2 gene has been associated with addiction in humans, said Dr. Heping Zhang, the paper’s senior author. The gene identified by the researchers had previously been associated with addictive behavior in mice. “This information can be used to design preventive and/or treatment strategies for addiction by controlling the environment exposure in the targeted group and/or by exploring and developing medications that modify the expression of the gene,” Dr. Zhang said. The researchers emphasized that their findings indicate that the associations are not as significant when individual outcomes for addiction are considered, underscoring the importance of considering multiple addiction types. The work was reported on August 31 in the early online edition of PNAS. [Press release] [PNAS abstract]

Epigenetic Changes Linked to Type 2 Diabetes

A research group at the Karolinska Institute in Sweden has shown that a key gene (PGC-1alpha) in the muscle cells of type 2 diabetics is chemically modified through DNA methylation. The scientists found that the gene was hypermethylated and had reduced expression in muscle cells taken from patients with early-onset type 2 diabetes. PGC-1alpha controls other genes that regulate the metabolism of glucose by the cell. DNA methylation is a form of epigenetic regulation, a process involving chemical modifications that are imposed externally on genes and that alter their activity without any change to the underlying DNA sequence. "This type of epigenetic modification might be the link that explains how environmental factors have a long-term influence on the development of type 2 diabetes," said Dr. Juleen Zierath, who led the study. "It remains to be seen whether the DNA methylation of this gene can be affected by, say, dietary factors." This work was published in the September 2 edition of Cell Metabolism. [Press release] [Cell Metabolism abstract]

Tbx5 Gradient Key to Development of Four-Chambered Heart

Research in turtles and lizards has revealed a tantalizing clue to the evolution of the four-chambered heart and the related ability of birds and mammals to lead a warm-blooded existence. The key appears to be varied expression of the transcription factor gene Tbx5 in the ventricles. In humans and other mammals, Tbx5 levels are high in the left ventricle and low in the right. The boundary of high and low is right at the septum, which forms to separate the two ventricles. When the researchers looked at the green anole lizard, which has just a three-chambered heart, they found that Tbx5 activity was essentially the same throughout the single ventricle and stayed the same throughout heart development. In the turtle, however, which has a primitive septum that partially separates its ventricle into left and right sides, distribution of Tbx5 was gradually restricted to the left side of the ventricle, resulting in a left-right gradient of Tbx5 activity. Further experiments in genetically engineered mice conclusively showed that a sharp line demarcating an area of high levels of Tbx5 is critical to induce formation of a septum between the two ventricles. "This is the first genetic link to the evolution of two, rather than one, pumping chamber in the heart, which is a key event in the evolution of becoming warm-blooded," said Dr. Benoit Bruneau, the senior author of the study. "The gene involved, Tbx5, is also implicated in human congenital heart disease, so our results also bring insight into human disease." The work was featured as the cover story of the September 3 issue of Nature.

Discovery of RAF Activation Mechanism May Aid Cancer Drug Development

A research team has shown that dimerization is essential for activation of the RAF protein kinase. When mutated, RAF protein kinase is responsible for more than 25 percent of human cancers. The research team believes that, by targeting the key dimerization process (specifically, the side-to-side dimerization of the kinase domain), it may be possible to develop new, more effective cancer therapies. "Protein kinases are the targets for some of the most successful anti-cancer drugs in the clinic," said Dr. Frank Sicheri, an author of the report. "Now that we have discovered how to turn off the RAF protein without interfering with other proteins, we may be able to design drugs that have unprecedented precision in targeting cancer cells while reducing the toxic side effects for patients." This work was published online in Nature on September 2. [Press release] [Nature abstract]

Teeth-Venom Combination Key to Lethality of Komodo Dragon Bite

A new study has shown that the effectiveness of the Komodo Dragon bite owes to a combination of highly specialized serrated teeth and venom. The authors dismiss the widely accepted theory that prey die from septicemia caused by toxic bacteria living in the dragon's mouth. Using sophisticated medical imaging techniques, an international team led by Dr. Bryan Fry from the University of Melbourne has shown that the Komodo Dragon has the most complex venom glands yet described for any reptile. The researchers conducted a comprehensive study of the Komodo Dragon bite, employing computer techniques to analyze stress in a dragon's jaws, and compared the results to those obtained for a crocodile. The dragons were found to have much weaker bites than crocodiles, but magnetic resonance imaging (MRI) of a preserved dragon head revealed complex venom glands and specialized serrated teeth which create deep lacerations for entry of the venom. "These large carnivorous reptiles are known to bite prey and release them, leaving the prey to bleed to death from the horrific wounds inflicted. We have now shown that it is the combined arsenal of the Komodo Dragon's tooth and venom that account for their hunting prowess," said Dr. Fry. "The combination of this specialized bite and venom seems to minimize the Dragon's contact with its prey and this allows it to take large animals." Komodo Dragons are native to the islands of Indonesia, with adult males weighing over 100 kg, and exceeding 3 meters in length. They have approximately 60 highly serrated teeth which are frequently replaced during their lifetime. The new research was published in the June 2 issue of PNAS. [Press release] [PNAS abstract]

Three Genes Responsible for Coat Texture in Dogs

Researchers have found that variants in just three genes, acting in different combinations, appear to account for the wide range of coat texture seen in dogs. The study involved genome-wide SNP association analysis carried out in 1,000 individual dogs representing 80 breeds. "What's important for human health is the way we found the genes involved in dog coats and figured out how they work together, rather than the genes themselves," said senior author Dr. Elaine A. Ostrander, chief of the Cancer Genetics Branch in the National Human Genome Research Institute. "We think this approach will help pinpoint multiple genes involved in complex human conditions, such as cancer, heart disease, diabetes, and obesity." The authors noted that their work illustrates that an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes. Specifically, the researchers found that an alteration in the RSPO2 gene results in wiry hair that grows in a pattern that gives the dogs a mustachioed look with long details called furnishings. Examples of dogs with wiry coats are Scottish terriers, Irish terriers and schnauzers. Long hair that is silky or fluffy was linked to a variant in the FGF5 gene. Cocker spaniels, Pomeranians and long-haired Chihuahuas are examples of dogs with long coats. A variant in the KRT71 gene produces curly coated dogs, such as the Irish water spaniel. Finally, if all three variants are present, a dog has a long and curly coat with furnishings. Examples of this type of breed include poodles and Portuguese water dogs. This work was published online in Science on August 27. [Press release] [Science abstract]

Bacterial Enzyme May Be New Antibiotic Target

Researchers have shown that inhibition of a key bacterial enzyme may be an effective approach for killing or suppressing the growth of a broad range of bacterial pathogens. The enzyme is nicotinate mononucleotide adenylyltransferase (NadD), an essential enzyme for nicotinamide adenine dinucleotide (NAD) biosynthesis. NAD has many crucial functions in nearly all important pathogens and the bacterial NadD differs significantly from the human enzyme. “It’s clear that because of bacterial resistance, we need new, wide-spectrum antibiotics,” said Dr. Andrei Osterman, senior author of the report. “This enzyme is indispensable in many pathogens, so finding ways to inhibit it could give us new options against infection.” In their work, the researchers identified small molecule compounds that efficiently inhibited target NadD enzymes from Escherichia coli (ecNadD) and Bacillus anthracis (baNadD), but had no effect on functionally equivalent human enzymes. The results of this study help validate NadD as a target for the development of antibacterial agents with potential broad-spectrum activity, the scientists said. This research was reported in the August 28 issue of Chemistry & Biology. [Press release] [C&B abstract]

Small Peptide Blocks Human Lung Cancer Growth in Mice

Scientists have shown that a small peptide [angiotensin-(1-7)] can block the growth and shrink the size of human lung cancer xenografts in mice. The study is the first to show that a specific peptide reduces lung tumor growth by inhibiting blood vessel formation. Angiotensin-(1-7) works by inhibiting the production of signals sent out by a tumor for food. The signals prompt blood vessels to grow and invade the tumor to feed it. Over the course of the current study, the tumors treated with angiotensin-(1-7) shrank, while saline-treated tumors grew and, at the end of the study, the tumors treated with angiotensin-(1-7) weighed about 60 percent less than the tumors treated with saline. Analysis also showed that the tumors from mice treated with the peptide had significantly fewer blood vessels compared to the tumors from the saline-treated animals. The authors said the treatment likely has applications beyond lung cancer--they have collected data showing it is effective on breast, colon, and brain tumors, as well. The treatment also presents an attractive possibility for future human cancer therapy from a cost perspective, the authors said. "Because it's a peptide, it's very small and can be made very easily," Dr. Gallagher noted. "We sometimes like to say we're the aspirin of cancer therapy." The article was published in the June issue of Molecular Cancer Therapeutics. [Press release] [MCT abstract]

Potential Non-Invasive DNA Test for Gastric and Colorectal Cancers

Preliminary testing of methylation patterns in two gene promoters in fecal DNA indicates that this might be a feasible non-invasive approach to detecting gastric and colorectal cancers. The researchers found that extensive methylation of the RASSF2 and SFRP2 gene promoters was much more likely to be found in advanced gastric tumors and colorectal tumors than in normal tissue. Methylation markers were detected in 57% of gastric cancer patients, 75% of colorectal cancer patients, and 44% of subjects with advanced colorectal adenomas, but only 10.6% of patients with none of these cancers. Because many patients are reluctant to undergo invasive tests for the detection of gastrointestinal cancers, the development of non-intrusive screening tests is desirable. Especially in cancer patients, some cells are sloughed off from the gastrointestinal tract, so small amounts of DNA from these cells present in stool samples can be examined for the presence of cancer biomarkers. "Selection of adequate biomarkers is critical to the success of any screening methodology," the authors wrote. "By identifying disease-specific methylation patterns for human fecal DNA from advanced gastric and colorectal tumors, we could more accurately identify subjects at high risk for developing, or having developed, advanced tumors." This work was published online on August 21 in the Journal of the National Cancer Institute. [Press release] [JNCI abstract]

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