Nutrition experts at Oregon State University have essentially “cured” laboratory mice of mild, diet-induced diabetes by stimulating the production of a particular enzyme. The findings could offer a new approach to diabetes therapy, experts say, especially if a drug could be identified that would do the same thing, which in this case was accomplished with genetic manipulation.
Increased levels of this enzyme, called fatty acid elongase-5, restored normal function to diseased livers in mice, restored normal levels of blood glucose and insulin, and effectively corrected the risk factors incurred with diet-induced diabetes. “This effect was fairly remarkable and not anticipated,” said Donald Jump, a professor of nutrition and exercise sciences at Oregon State, where he is an expert on lipid metabolism and principal investigator with OSU’s Linus Pauling Institute. “It doesn’t provide a therapy yet, but could be fairly important if we can find a drug to raise levels of this enzyme,” Jump said. “There are already some drugs on the market that do this to a point, and further research in the field would be merited.”
The studies were done on a family of enzymes called “fatty acid elongases,” which have been known of for decades. Humans get essential fatty acids that they cannot naturally make from certain foods in their diet. These essential fatty acids are converted to longer and more unsaturated fatty acids. The fatty acid end products of these reactions are important for managing metabolism, inflammation, cognitive function, cardiovascular health, reproduction, vision and other metabolic roles.
The enzymes that do this are called fatty acid elongases, and much has been learned in recent years about them. In research on diet-induced obesity and diabetes, OSU studied enzyme conversion pathways, and found that elongase-5 was often impaired in mice with elevated insulin levels and diet-induced obesity.
The scientists used an established system, based on a recombinant adenovirus, to import the gene responsible for production of elongase-5 into the livers of obese, diabetic mice. When this “delivery system” began to function and the mice produced higher levels of the enzyme, their diet-induced liver defects and elevated blood sugar disappeared.
“The use of a genetic delivery system such as this was functional, but it may not be a permanent solution,” Jump said. “For human therapy, it would be better to find a drug that could accomplish the same thing, and that may be possible. There are already drugs on the market, such as some fibrate drugs, that induce higher levels of elongase-5 to some extent.”
There are also drugs used with diabetic patients that can lower blood sugar levels, Jump said, but some have side effects and undesired complications. The potential for raising levels of elongase-5 would be a new, specific and targeted approach to diabetes therapy, he said. While lowering blood sugar, the elevated levels of elongase-5 also reduced triglycerides in the liver, another desirable goal. Elevated triglycerides are associated with “fatty liver,” also known as non-alcoholic fatty liver disease. This can progress to more severe liver diseases such as fibrosis, cirrhosis and cancer.
Further research is needed to define the exact biological mechanisms at work in this process, and determine what the fatty acids do that affects carbohydrate and triglyceride metabolism, he said. It appears that high fat diets suppress elongase-5 activity.
“These studies establish a link between fatty acid elongation and hepatic glucose and triglyceride metabolism,” the researchers wrote in their report, “and suggest a role for regulators of elongase-5 activity in the treatment of diet-induced hyperglycemia and fatty liver.”
The study was published in the Journal of Lipid Research. The research was supported by the National Institutes of Health and the National Institute for Food and Agriculture of the U.S. Department of Agriculture.
“This protein is present in the part of the brain in which memories are stored. We have found that in order for any memory to be laid down this protein, called the M3-muscarinic receptor, has to be activated.
“We have also determined that this protein undergoes a very specific change during the formation of a memory – and that this change is an essential part of memory formation. In this regard our study reveals at least one of the molecular mechanisms that are operating in the brain when we form a memory and as such this represents a major break through in our understanding of how we lay down memories.
“This finding is not only interesting in its own right but has important clinical implications. One of the major symptoms of Alzheimer's disease is memory loss. Our study identifies one of the key processes involved in memory and learning and we state in the paper that drugs designed to target the protein identified in our study would be of benefit in treating Alzheimer's disease.”
Professor Tobin said there was tremendous excitement about the breakthrough the team has made and its potential application: “It has been fascinating to look at the molecular processes involved in memory formation. We were delighted not only with the scientific importance of our finding but also by the prospect that our work could have an impact on the design of drugs for the treatment of Alzheimer's disease.”
One article warns that the absence of major investments in new technology and prevention and treatment tools could make drug-resistant strains of TB the “dominant” form of TB over the coming decades, according to the news service (5/18). The article notes “that India and China had around 50 percent of the global MDR-TB burden, followed by Russia with 9 percent,” Reuters writes. The authors write, “The future possibility of strains that are totally resistant to all anti-tuberculosis drugs is not inconceivable.”
“In other studies in the series … scientists said the combined impact of new drugs, vaccines, and diagnostic tests could cut worldwide incidence of TB by 94 percent by 2050,” the news service reports. According to experts, only about a quarter of the funding needed for drug research and development is available.
“Development of new drugs for TB is lengthy, expensive, and risky, and the expected revenues are too small to justify commercial investment,” Zhenkun Ma of the Global Alliance for TB Drug Development and co-authors write in a paper. “New financing and market incentive mechanisms are needed.”
The journal also notes that “there are 11 potential TB vaccines being tested in human trials and up to 10 experimental medicines in the TB drug 'pipeline.' Since many drugs fail in late-stage trials, this handful of possibilities is unlikely to be enough,” Reuters reports (Kelland, 5/18).
The series also focused on the broader issues that contribute to the spread of TB, the Associated Press reports. “Experts said TB isn't only a medical problem, but is intertwined with poverty, as it spreads widely among people living in overcrowded, dirty places. They said TB programs need to go beyond health and include other sectors like housing, education and transportation,” the news service writes. Philip Stevens, a health policy expert at the International Policy Network, said the disease “cannot be tackled in isolation,” noting that the focus of control efforts should be on “economic growth, which is outside the control of the U.N.” (Cheng, 5/18).
“In the eighth and final paper … a call to action is made to a wide range of sectors to assist scale-up TB service delivery, research and control. The launch of The Lancet TB Observatory, which will monitor progress on key indicators on an ongoing basis, is also announced,” according to a Lancet press release. The Observatory, which is a collaboration between the Lancet, the Stop TB Parternship, the WHO and the Global Fund to Fight AIDS, Tuberculosis, and Malaria, “will assess and monitor” TB research, financing and other information. In a comment discussing the Observatory, Lancet Editor-in-Chief Richard Horton and Executive Editor Pamela Das observe that currently “there is no formal mechanism to assess this information critically and independently. Nor is there any means to hold the various stakeholders in tuberculosis control to account” (5/18).
The series also includes comments about how to scale-up an integrated TB and HIV response, the burden of the disease in women and children and how migration patterns within and between countries contribute to the spread of TB.