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Insulin Resistance Linked to Fat & Protein Intake -
Insulin Resistance Linked to Protein 'Signature'
  MedPage Today
April 07, 2009
TORONTO, April 7 -- Eating a lot of fat can lead to insulin resistance but, surprisingly, so will adding meat-based protein to the diet.
Action Points
* Explain to interested patients that the adverse impact of a high-fat diet on insulin sensitivity is well known.
* Note that this study suggests that a diet including fat and branched-chain amino acids -- found in dairy product and meats -- may also induce insulin resistance.
That's the implication of a range of observations in lean and obese humans, followed by experiments in rats, according to Christopher Newgard, Ph.D.., of Duke University Medical Center in Durham, N.C., and colleagues.
The human studies showed that obese people had several metabolic differences from their leaner counterparts, including increased levels of the so-called branched-chain amino acids leucine, isoleucine and valine, Dr. Newgard and colleagues wrote in the April issue of Cell Metabolism.
Those amino acids -- some of the 20 building blocks of protein -- are found in large amounts in dairy products and red meat.
The animal studies showed that rats fed a diet high in fat and branched-chain amino acids gained only a little more weight than animals fed a normal chow diet, while those on a high-fat diet only gained significantly more.
But the rats eating fat and protein were as insulin resistant as the animals fed a high-fat diet.
"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," Dr. Newgard said in a statement.
But, he added, "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."
Problems may arise, though, "if you add a lot of unneeded protein to a fatty diet," he said. "The ancient Greeks were right: everything in moderation."
The researchers set out to understand metabolic, endocrine, inflammatory, and physiologic differences between obese and lean subjects.
In a cohort of 73 obese and 67 lean volunteers, they measured 19 hormones involved in energy balance and fuel homeostasis, four pro- and anti-inflammatory cytokines, variables such as insulin sensitivity, body composition, and resting metabolic rate, and a range of more than 100 metabolites..
As expected, the obese volunteers were significantly less insulin sensitive than their lean counterparts. The homeostasis model assessment (HOMA) index was 2.3 times higher than in lean controls, which was significant at P<0.0001.
And in a subset of participants who had intravenous glucose tolerance testing, the insulin sensitivity index was 2.1-fold higher in lean subjects, which was significant at P<0.001.
But the key finding was that obese volunteers had a "signature" -- consisting of branched-chain amino acids and their metabolites -- that was significantly associated with a higher HOMA index (at P<0.001).
Because of that observation, Dr. Newgard and colleagues fed rats on three different diets -- a standard chow, a high-fat diet, and a diet high in fat and branched-chain amino acids.
After 13 weeks, the high-fat rats were 70% heavier than they were at the start, compared with 51% and 49% for the fat/protein and standard chow animals, respectively. The difference between the high-fat group and the others was significant at P<0.039.
The difference in weight gain between the two high-fat groups was mainly caused by rates of food intake -- rats in the high-fat group ate an average of 746 kilocalories a week compared with 666 for the animals getting fat and protein. (The chow-fed rats averaged 782 kilocalories a week, but were more active than the fat/protein animals, accounting for the similar weight gain.)
The fat/protein group had increases of up to 150% in leucine and isoleucine and 109% in valine, compared with the other two groups.
Despite gaining weight at a rate similar to the chow-fed animals, the rats fed high fat and protein were as insulin resistant (on glucose and insulin tolerance tests) after 15 weeks as the high-fat-fed animals.
To rule out the possibility that it was the fat and not the branched-chain amino acids that were responsible, the researchers conducted a second feeding test.
Three groups of animals were allowed to feed at will on standard chow, a high-fat diet, and a high-fat diet with additional branched-chain amino acids.
A fourth group was fed a high-fat diet, but only allowed to eat as much as their counterparts in the high-fat/protein group.
As expected, the fourth group had body weights identical to the high-fat/protein group and not significantly different from the chow-fed animals.
But intravenous glucose tolerance testing showed clear insulin resistance in the high-fat and fat/protein group, but not in the other two groups, demonstrating that moderate fat intake is not enough to induce insulin resistance, the researchers said.
Dr. Newgard and colleagues said more research is needed before dietary advice can be given but, overall, the results suggest that "in the context of a dietary pattern that includes high-fat consumption, (food containing branched-chain amino acids) may make an independent contribution to development of insulin resistance and diabetes."
The study was supported by GlaxoSmithKline and the NIH. The researchers reported no conflicts.
Primary source: Cell Metabolism
Source reference:
Newgard CB, et al "A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance" Cell Metabolism 2009; 9: 311-326.
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