April 2009 - A clue about the blood chemistry of obese people who develop insulin resistance, a precursor to diabetes, has been confirmed in animal studies at the Duke University Medical Center.
Obese people have been found to harbor proteins called branched-chain amino acids (BCAAs) at far higher levels than non-obese people. The suspicion has been that these amino acids, in combination with a high-fat diet, contribute to insulin resistance.
The team found that the BCAA signature in obese humans consisted of the branched-chain amino acids themselves, plus a cluster of several products related to the body's breakdown processes for BCAA.
"In the case of the amino acids, we also are finding increased levels of their metabolic breakdown products, which suggests the whole system for handling the amino acid metabolic process has been overloaded," said senior author Christopher Newgard, Ph.D., director of the Sarah W. Stedman Nutrition and Metabolism Center and W. David and Sarah W. Stedman Distinguished Professor at Duke. "Our rat studies show that this overload causes changes at the cellular level that can lead to insulin resistance."
To determine whether the BCAA signature in obese humans might signal that their intake is harmful, the scientists performed a feeding study in rats that showed an independent contribution of BCAAs to insulin resistance.
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"These findings, however, would need to be confirmed in studies with people before any dietary recommendations could be issued," said Laura Svetkey, M.D., director of the Duke Hypertension Center, director of clinical research at the Sarah W. Stedman Nutrition and Metabolism Center, and co-senior author of the study, published in Cell Metabolism.
"Insulin resistance occurred in animals with a diet high in the branched-chain amino acids, but only if they were ingested along with a high level of fat in the diet," Newgard said. Because obese humans tend to ingest high-fat diets, the combination of high-BCAA and high-fat intake might contribute to insulin resistance in obese humans, but additional studies are needed. BCAAs comprise as much as 25 percent of amino acids in dietary protein, and are particularly enriched in diets high in animal (meat) proteins.
"I want to be clear that our animal data suggest that there is nothing wrong with obtaining protein from sources that are high in branched-chain amino acids, as long as you are not eating beyond what your energy needs are," said Newgard, who is a professor of pharmacology and cancer biology and professor of medicine at Duke. "If you add a lot of unneeded protein to a fatty diet, perhaps that's where you get into problems. The ancient Greeks were right: everything in moderation."
Insulin resistance happens when insulin, released by the beta cells in the pancreas, doesn't work normally to stimulate glucose uptake into tissues.
Rats on a high-fat diet gained substantially more weight than rats that ate BCAAs with high-fat chow or those that ate standard chow. However, the rats eating the high-fat diet with BCAA became as insulin resistant as rats fed a high-fat only diet, even though they weren't eating as much.
To make sure that the BCAAs and not high fat contributed to insulin resistance, the researchers let animals feed freely on the standard chow, high-fat, or high fat with BCAA diets, and added a fourth group of rats fed a high-fat chow diet in an amount that matched the lower rate of food intake in the high-fat BCAA group. Studies showed clear insulin resistance in the high-fat and high-fat with BCAA groups, but not in the rats eating less of the high fat chow or those eating standard chow. This proved that moderate fat intake was not a cause of insulin resistance.
The researchers also showed that BCAAs contributed to insulin resistance by chronically activating mTOR, a signaling protein that regulates cell growth and survival and that functions as a sensor of cellular nutrient and energy levels. When the rats had the drug rapamycin, which blocks mTOR, their insulin resistance was reversed.
Next the team will study what happens when obese people who have insulin resistance lose weight and "whether there is a parallel improvement in the BCAA metabolic signature in the blood," Newgard said.
Svetkey added, "We also need to study the relationship between dietary intake of BCAA and insulin resistance in humans, and whether changing dietary patterns, beyond weight control, can improve matters."
The study was supported by a sponsored research agreement from Glaxo SmithKline and NIH grants. Authors Jie An, James Bain, Michael Muehlbauer, Robert D. Stevens, Lillian Lien, Andrea Haqq, Michelle Arlotto, Olga Ilkayeva, Brett Wenner, David Millington and Mark D. Butler are with the Sarah W. Stedman Nutrition and Metabolism Center. Lillian Lien, Svati Shah, Cris Slentz, William Yancy Jr. and Gerald Musante are with the Duke Department of Medicine. Jie An is with the Duke Department of Pharmacology and Cancer Biology. Andrea Haqq and David Millington are with the Duke Department of Pediatrics. James Rochon and Dianne Gallup are with the Duke Department of Biostatistics and Informatics. Howard Eisenson is with Duke Community and Family Medicine, and Richard Surwit is the Duke Department of Psychiatry.
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Source: Duke University Medical Center