The discovery of a previously unknown effect of the amino acid alanine on cell metabolism could lead to new drugs for short-term control of blood glucose.

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Could an amino acid provide clues to diabetes?

Amino acids are small building block molecules that the body uses to make proteins. Alanine is classed as a nonessential amino acid because the body can make it without having to source it from food.

Scientists at the Joslin Diabetes Center and Harvard Medical School, both in Boston, MA, have now uncovered a new and unique role for alanine by studying it in laboratory cells and mice.

It appears that the amino acid activates an enzyme called AMP kinase (AMPK) that increases energy production in cells. This results in a short-term reduction in blood glucose that does not involve insulin.

A study paper about the findings now features in the journal Molecular Metabolism.

“AMPK,” says senior study author Dr. Mary-Elizabeth Patti, who is an associate professor of medicine at Harvard Medical School and an investigator at the Joslin Diabetes Center, “is an enzyme in cells throughout the body that is activated when nutrient supplies are low, or in response to exercise.”

It is possible that the discovery about alanine’s effect on AMPK could eventually lead to a pill that a person can swallow before a meal to exert a temporary effect on glucose metabolism.

“However, this is early-stage research, and we need to test the concept both in mice and ultimately in humans,” Dr. Patti adds.

Scientists already knew that AMPK helps regulate metabolism at the cell, tissue, and systemic level in response to nutrient levels.

AMPK achieves this in several ways. In cells, for instance, when it receives the trigger signal, it switches on genes that ramp up energy production.

“AMPK is a good thing,” Dr. Patti explains, “and it also can be activated by a variety of treatments for type 2 diabetes, such as metformin.”

Type 2 diabetes develops from insulin resistance, a condition in which the body does not respond properly to insulin, the hormone that helps cells absorb and use blood sugar, or glucose.

Around 90–95 percent of the 30 million people in the United States with diabetes have type 2. Although type 2 diabetes typically occurs after the age of 45, it is becoming increasingly common in younger adults and children.

Dr. Patti and her team wanted to find out whether any particular amino acids activated AMPK. They also wanted to understand how the trigger mechanism works at the cell and systemic level.

They started by screening several amino acids using rat liver cells. They used liver cells because the liver plays a key role in controlling glucose in the body.

“Alanine was the one amino acid that was consistently able to activate AMPK,” Dr. Patti notes.

In the next stage of the study, the team confirmed that alanine was triggering AMPK’s metabolic activity. They also ran tests to confirm this in liver cells from humans and mice.

All the tests showed that alanine triggered AMPK in rat, mouse, and human liver cells, regardless of whether the glucose levels in the cells were high or low.

The scientists then ran tests on live mice. They saw that levels of AMPK in the mice went up when they gave the animals oral doses of alanine. They also found that mice given alanine before receiving a glucose dose developed lower levels of glucose.

Further tests revealed that the same mechanism was present in mice with and without obesity, even though glucose often metabolizes differently in under- and overweight mice.

In a final set of experiments, the researchers revealed that the changes in glucose levels were not the result of insulin and glucagon secretion. Instead, they were due to AMPK helping the liver use glucose and release less of it by changing a cell metabolism process.

All these data together suggest that amino acids, and specifically alanine, may be a unique potential way to modify glucose metabolism.”

Dr. Mary-Elizabeth Patti