All Posts tagged metabolism

New approach for diabetes therapy

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.

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Poor Diet Metabolism, Lack of Exercise Increases Asthma Risk in Kids

Metabolic syndrome is a cluster of risk factors which can result in heart disease and diabetes. Researchers have now found that poor diet and lack of exercise that lead to an imbalance in metabolism may also increase a child's risk of developing asthma.

Dr. Giovanni Piedimonte and researchers from West Virginia University School of Medicine analyzed data from nearly 18,000 children aged 4 to 12 years who were taking part in the Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) project. Factors considered included triglyceride levels and evidence of acanthosis nigricans, which are raised patches of brown skin that are often biomarkers for insulin resistance.

The team also considered body mass index or BMI, and almost 21% of the children were considered obese. Fourteen percent of the children had asthma.

The researchers found that asthma prevalence among the children was strongly associated with certain symptoms of metabolic syndrome including dyslipidemia and abnormal glucose metabolism, but not weight status. Although those who were obese were more likely to have asthma, even children of a healthy weight who had imbalanced metabolism were at increased risk.

Certain metabolic factors participate in the asthma disease process by contributing to inflammation of the airways in the lungs and hyperreactivity (contraction of smooth muscle in the bronchial walls), says Dr. Piedimonte. He says that strict monitoring and control of triglyceride and glucose levels early in life may play a role in the management of chronic asthma in children.

Dr. Piedimonte would like to see the findings used as further support for universal lipid screening in children. “The rationale is that by using selective screening, we would have missed over a third of children with significant genetic dyslipidemia,” he said.

Both poor diet – one lacking in antioxidants but high in fat – and inadequate exercise play a role in the metabolic syndrome, a group of risk factors that increase the risk for coronary artery disease, stroke, and type 2 diabetes. The goal of treatment is often weight loss (if overweight), a minimum of 30 minutes of daily moderate intensity exercise, and a lowering of cholesterol, blood pressure and blood sugar through diet or medication.

Source reference:
Cottrell L, et al “Metabolic abnormalities in children with asthma” Am J Respir Crit Care Med 2010; DOI: 10.1164/rccm.201004-0603OC.

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A high fat diet can disrupt our biological clock

To examine this thesis, Froy and his colleagues, Ph.D. student Maayan Barnea and Zecharia Madar, the Karl Bach Professor of Agricultural Biochemistry, tested whether the clock controls the adiponectin signaling pathway in the liver and, if so, how fasting and a high-fat diet affect this control. Adiponectin is secreted from differentiated adipocytes (fat tissue) and is involved in glucose and lipid metabolism. It increases fatty acid oxidation and promotes insulin sensitivity, two highly important factors in maintaining proper metabolism.

The researchers fed mice either a low-fat or a high-fat diet, followed by a fasting day, then measured components of the adiponectin metabolic pathway at various levels of activity. In mice on the low-fat diet, the adiponectin signaling pathway components exhibited normal circadian rhythmicity. Fasting resulted in a phase advance. The high-fat diet resulted in a phase delay. Fasting raised and the high-fat diet reduced adenosine monophosphate-activated protein kinase (AMPK) levels. This protein is involved in fatty acid metabolism, which could be disrupted by the lower levels.

In an article soon to be published by the journal Endocrinology, the researchers suggest that this high-fat diet could contribute to obesity, not only through its high caloric content, but also by disrupting the phases and daily rhythm of clock genes. They contend also that high fat-induced changes in the clock and the adiponectin signaling pathway may help explain the disruption of other clock-controlled systems associated with metabolic disorders, such as blood pressure levels and the sleep/wake cycle.

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Probiotics Could Benefit Metabolic Syndrome

Metabolic syndrome (MetS) is a condition characterised by central obesity, hypertension, and disturbed glucose and insulin metabolism. The syndrome has been linked to increased risks of both type 2 diabetes and cardiovascular diseases.

Gut microflora and metabolic syndrome

“The recent discovery by our group that patients feeding a fat-enriched diet develop diabetes and obesity through changes of their intestinal microflora has led us to envision innovative strategies aiming to hamper the development of the deleterious intestinal bacterial ecology observed during metabolic diseases,” said Professor Remy Burcelin of INSERM, who led the study.

The current study involved administering the probiotic strain B420 to diabetic mice on a high-fat diet. According to the researchers, the probiotic improved the fasting glycaemia and restored the glucose turnover rate to the level of the control mice fed with normal chow.

“Importantly, the probiotic treatment reduced the fasted insulin levels, but improved the insulin secretion upon glucose challenge, indicating an improved metabolic flexibility and restoration of normal glucose metabolism, and a potential beneficial effect on metabolic syndrome,” said Danisco.

The company added that the beneficial effect of B420 is mediated by a reduction of the pro-inflammatory molecule, plasma lipopolysaccharide (LPS). “B420 changes intestinal mucosal microbiota and reduces the efflux of LPS into plasma, thereby reducing inflammation and improving insulin metabolism,” it said.

Probiotics and obesity

A breakthrough paper published in Nature in December 2006 reported that microbial populations in the gut are different between obese and lean people, and that when the obese people lost weight their microflora reverted back to that observed in a lean person, suggesting that obesity may have a microbial component.

More findings on the topic have since trickled through the scientific web. At a scientific symposium organised by the Beneo Group in April 2008, Dr. Kieran Touhy from the University of Reading noted that obese animals have significantly lower bifidobacteria levels than their lean counterparts, which suggests potential for prebiotic fibres since the growth of these bacteria is selectively promoted by inulin and fructooligosaccharides.

Dr. Nathalie Delzenne from the Catholic University of Louvain in Belgium and Dr. Robert Welch from the University of Ulster presented results from animal and human studies, respectively, which indicated the potential of prebiotic supplementation to regulated food intake.

“This is an interesting new research area which may open up new opportunities for functional foods in the future,” said Dr Julian Stowell, head of scientific affairs for Danisco's Health and Nutrition Platform.

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