Improved Glycemic Control Through Reduction of Specific Dietary Amino Acids

Our findings highlight an important new avenue of investigation—specifically, how dietary quality at the level of individual amino acids, not simply the quantity of food consumed, regulates metabolic health. Our findings may be highly translatable to the clinic through the use of diet plans or through the prescription of already FDA-approved medical foods lacking specific branched-chain amino acids.

At a Glance

Diabetes costs Wisconsin over $6 billion in health care costs each year. Diabetes is a particularly acute problem for minority groups in our state, affecting over 40 percent of American Indian and 20 percent of African American adults. Altogether, nearly two million Wisconsin residents are estimated to have diabetes or pre-diabetes, which are associated with diet and obesity. Because of this, dietary interventions that promote blood sugar control and a healthy weight are needed.

The researchers found that reducing dietary levels of three amino acids restored blood sugar control and normal body composition in obese, insulin-resistant mice, even if they consumed a high-fat, high-sugar diet. Further research will test the translatability of the findings to humans.

The Challenge

Diabetes and obesity are major public health challenges in Wisconsin and the United States. Regulating one’s diet is important for managing both, however, common dietary advice may be counterproductive for combating these conditions. One reason for this is that protein is typically perceived as beneficial, but evidence suggests that people who eat less protein are actually at lower risk of diabetes, obesity, and cancer, and may live longer.

Putting overweight individuals on low-protein diets helps them lose weight and decrease blood sugar, but specific amino acids (protein building blocks) may be more important than protein itself to maintaining a healthy weight and blood sugar. This study examined the role of the three branched-chain amino acids (leucine, isoleucine, and valine) in promoting metabolic health.

Project Goals

The project aimed to better understand the impact of the amino acid composition of the diet on glycemic control, metabolism and weight gain, and examine the potential efficacy of altered dietary amino acid intake as a sustainable intervention to improve blood sugar levels and minimize weight gain.

Specifically, multiple experimental trials were conducted in which different groups of pre-diabetic, obese mice were fed different diets, designed to elucidate the relationship between amino acid consumption, glycemic control and weight loss.

The mice were fed diets that either resembled high-calorie, high-fat “Western diets,” Western diets supplemented with additional branched-chain fatty acids, Western diets that were low in amino acids, Western diets low in branched-chain amino acids, and a control diet of regular lab mouse food.

Results

The research generated new insight into the molecular mechanisms by which dietary branched-chain amino acids promote metabolic health. The study found that reducing dietary levels of the three branched-chain amino acids (leucine, isoleucine, and valine) rapidly restored blood sugar control and normal body composition to obese, insulin-resistant mice, even if they continued to consume a high-fat, high-sugar diet. The researchers also determined that isoleucine, and to a lesser extent valine, mediate the beneficial effects of restricting dietary branched-chain amino acids in lean mice.

Reduced consumption of these amino acids leads to weight loss not through reduced calorie intake, but rather through increased energy expenditure. This is because the hormone FGF21, which regulates glucose metabolism and energy expenditure, is induced in both humans and mice in response to a low protein diet. Another key finding was that lipid droplet sizes in the liver also tracked with branched-chain amino acid consumption, with mice that ate Western diets and branched-chain amino acids having much more fat in their livers than mice who ate diets without branched-chain amino acids.

The work resulted in one patent application, contributed to eight peer-reviewed publications (the two publications which were centered directly on the work funded by the Partnership Program together received more than 100 citations), has led to the conduct of a human clinical trial to test the feasibility of reducing branched-chain amino acids in the human diet, and dozens of local, national, and international research presentations at conferences, symposia, and invited talks. Multimillion dollar funding for further related research on this topic has been granted to the PI by the U.S. Department of Veterans Affairs Office of Research and Development and the National Institutes of Health/National Institutes on Aging.

Lasting Impact

Collectively, the results demonstrated that reducing dietary levels of all amino acids, or specifically of leucine, isoleucine, and valine, can reverse obesity and metabolic problems resulting from high-fat, high-sugar diets without requiring calorie restriction in mice.

Experiments have already begun to test the translatability of the findings to humans. While the direct applicability of the results remains to be determined, there is a correlation between blood levels of branched-chain amino acids and obesity and insulin resistance in humans.

Thus, if dietary branched-chain amino acids have similar effects on energy balance and metabolism in humans, the findings could potentially lead to improved dietary recommendations and possibly medical treatments for Wisconsin residents.