How high fat foods impact diabetes and metabolic syndrome

ScienceDaily (May 22, 2012) — A University of Michigan Health System study provides new clues about the health-damaging molecular changes set in motion by eating high-fat foods.

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A better understanding of the body's response to indulgent eating could lead to new approaches for treating diabetes and metabolic syndrome. High-fat foods can contribute to obesity, which increases the risk for developing type 2 diabetes.

The researchers learned a key protein called Bcl10 is needed for the free fatty acids -- which are found in high fat food and stored in body fat -- to impair insulin action and lead to abnormally high blood sugar.

In the laboratory study, mice deficient in Bcl10 were protected from developing insulin resistance when fed a high-fat diet. The findings will be published May 31 in Cell Reports.

Insulin helps control blood sugar, but insulin resistance can lead to the abnormally high blood sugar levels that are the hallmark of diabetes. Insulin resistance can occur as part of metabolic syndrome, a cluster of conditions that increase the risk for type 2 diabetes and heart disease.

As millions of Americans become overweight and obese, type 2 diabetes and metabolic syndrome are on the rise.

"The study also underscores how very short-term changes in diet such as high-fat eating for only a few days, perhaps even less, can induce a state of insulin resistance," says senior study author Peter C. Lucas, M.D., Ph.D., associate professor of pathology at the University of Michigan Medical School.

Researchers began by investigating how free fatty acids induce inflammation and impair insulin action in the liver. It's thought the liver is a major target for the harmful effects of free fatty acids.

In the liver, free fatty acids undergo metabolism to produce diacylglycerols prior to inducing the inflammatory response. Diacylglycerols also activate NF-B signaling which has been linked with cancer, metabolic and vascular diseases.

The team of researchers concluded that Bcl10 is required for fatty acids to induce inflammation and insulin resistance. In the study, Bcl10-deficient mice showed significant improvement in regulation of blood sugar.

"We were surprised to learn that Bcl10, a protein previously known for its critical role in immune cell response to infection, also plays a critical role in the liver's response to fatty acid," says Lucas.. "This is an example of nature co-opting a mechanism fundamental to the immune system and using it in a metabolic organ, in this case, the liver."

"These findings reveal a new and important role for Bcl10 and could lead to novel ideas for treating patients with metabolic syndrome and type 2 diabetes," says co-senior author Linda M. McAllister-Lucas, M.D., Ph.D., associate professor of pediatric hemotology/oncology.

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New nutrition bar improves metabolic biomarkers linked to cardiovascular disease, cognitive decline, and anti-oxidant defenses in only two weeks

ScienceDaily (May 10, 2012) — Scientists at Children's Hospital Oakland Research Institute's (CHORI) Nutrition & Metabolism Center, led by National Medal of Science winner Bruce N. Ames, PhD, have developed a low-calorie fruit-based high fiber vitamin and mineral nutrition bar called the "CHORI-bar" that improves biological indicators (increased HDL-c and glutathione, lowered homocysteine) linked to risk of cardiovascular disease, cognitive decline, and associated decline in anti-oxidant defenses.

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The CHORI-bar is intended to help restore optimal nutritional balance in people eating poor diets, and to help transition them to healthier eating habits. The bar is satiating and at only approximately 110 calories per bar, may be helpful in weight reduction programs.

The first research report on the CHORI-bar will appear in the August 2012 FASEB Journal (the Journal of the Federation of American Societies for Experimental Biology) published online on May 1, 2012.

Low intake of many vitamins and minerals is widespread in the U.S. After years of studying the interactions of vitamins and minerals with metabolic processes, Dr.Ames became convinced that modest deficiencies could be contributing to metabolic imbalances that increase risk of diseases associated with obesity and aging, such as diabetes, cancer, and heart disease. In 2006, he proposed the Triage Theory that provided a mechanistic rationale connecting modest vitamin/mineral deficiencies with disease (2), which was strongly supported by subsequent analyses (3,4).

In 2003, Dr. Ames and his colleague Mark Shigenaga, PhD, whose research focuses on the impact of food on gut function, embarked on the development of the CHORI-bar, an economical, low calorie, food supplement that could restore metabolic balance. Intestinal health is now widely recognized to be an important determinant of overall health. Food components that benefit gut health, such as certain soluble fibers and polyphenols, also deficient in typical Western diets, were included in the bar along with a number of other ingredients, all aimed at helping to restore optimal nutrition. Dr. Ames assembled a team of scientists and a collaboration was initiated with the Processed Foods Unit at the United States Department of Agriculture, Agricultural Research Service in Albany, Calif. to assist in the production of a tasty and nutritious bar.

Since the project began, a series of bar formulations were developed, and to date 11 small pilot trials were conducted to refine components and improve palatability from an almost inedible start to a tasty bar. Improvements are continuing to expand the number of disease risk biomarkers favorably impacted by the bar.

The FASEB Journal report describes the prototype bar developed in this program and presents results of a 2-week trial in 25 generally healthy adults led by CHORI-bar team member and pediatric cardiologist Michele Mietus-Snyder, MD. The participants varied in ages and BMI and ate two bars each day for 2-weeks. Included in the panel of assays at the beginning and end of the trial, in addition to standard measures of lipids, glucose metabolism, and inflammation, was ion mobility analysis (developed by CHORI Senior Scientist Ronald Krauss, MD, (5)) used to quantify lipoprotein sub-fractions, and a liquid chromatography linked tandem mass-spectrometry (LD/MS/MS) assay (developed by CHORI Associate Staff Scientist Jung Suh, MPH, PhD (6)) to measure thiol compounds and amino acid metabolites. This expanded panel of assays permitted a more in depth look at biomarkers and at clues to mechanisms underlying effects of the CHORI-bar.

Impressively, favorable metabolic changes occurred after only 2-weeks of bar intake, without guidelines as to whether to use the bar as a meal replacement or a supplement. For example, increased HDL cholesterol has been reported after intake of several individual bar ingredients, but at much higher doses than what is present in the bar. The possibility that bar ingredients are acting additively or synergistically is supported by some preliminary evidence.

Two examples from the results of this trial emphasize the fact that, with the right mixture of food components, pharmacological or supraphysiological doses are not needed to positively move metabolism in a healthy direction.

1) It is difficult to both raise HDL and lower homocysteine either pharmacologically or with dietary interventions. "Heart-healthy" diets most consistently linked to an increase in HDL-c are those that emphasize fat quality more than quantity, such as the Mediterranean diet. The CHORI-bar combines aspects of the Mediterranean diet with the most biologically active form of folate (5-methyl-tetrahydrofolate). The latter is expected to bypass the need for high levels of folate required to keep homocysteine at a healthy level in individuals with the TT MTHFR polymorphism, which is present in half the U.S. population.

2) Glutathione is the principal regulator of the cellular redox environment, and is important for preventing oxidative stress. Glutathione declines with age and is low in many diseases. Few drugs and only high doses of certain food constituents have been reported to raise glutathione, but only 2-weeks consumption of the bar was required.

Current research is continuing on several fronts. In addition to its potential to have an impact on public health, the CHORI-bar is a research tool that can elucidate mechanisms by which food components in the bar interact with metabolic pathways to favorably impact disease-relevant biomarkers. Two additional bars have been developed that expand the number of biomarkers improved by the bar to include measures of insulin resistance, inflammation, and additional elements of lipid metabolism, notably LDL cholesterol. Efforts are underway to combine attributes of all 3 bars in a single bar. A series of clinical trials have also been initiated that test the efficacy of the CHORI-bar in improving metabolism in individuals with diseases accompanied by metabolic dysregulation favorably impacted by the bar, including obesity, asthma, and hypertension. And finally, development of additional biomarker assays is underway to expand the classes of metabolic changes that can be detected, such as several different types of DNA damage.

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