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Protein discovery

aP2 function could lead to new T2DM treatments

Researchers also identified a role for aP2 antibody
Drs Gökhan Hotamisligil (left) and Qiong Cao

A particular type of protein found in fat cells helps regulate how glucose is controlled and metabolised in the liver, according to researchers from Harvard School of Public Health. Using experimental models, the investigators found that switching off this protein leads to better control of glucose production from the liver, revealing a potential new target that may be used to treat type 2 diabetes and other metabolic diseases.

"The consequences of this discovery are profound, and the potential therapeutic applications by switching this protein off have the capability to reshape the way physicians treat diabetes," said lead author Dr Haiming Cao.

The research, which was published in the journal Cell Metabolism, sought to ask a conundrum: not all who are obese or resistant to insulin develop type 2 diabetes.

In fact, many patients who are severely obese never develop the disease. As a result scientists have theorised that an unknown factor is involved in regulating glucose metabolism in the liver, and perhaps the presence or absence of this element might determine who gets the disease.

"Although it has long been recognised that a key event leading to development of type 2 diabetes is uncontrolled glucose production from the liver, underlying mechanisms have been elusive," said senior author Dr Gökhan S Hotamisligil. "We now have identified aP2 as a novel hormone released from fat cells that controls this critical function."

In the new study, researchers first increased the levels of aP2 in normal, healthy mice to match the high blood aP2 levels seen in obese mice and humans. This resulted in impaired glucose metabolism.

They then reduced the blood aP2 levels in obese and diabetic mice to low levels seen in lean healthy mice. This intervention restored glucose metabolism to its normal status.

The investigators concluded that the amount and action of aP2 in blood was critical for diabetes, opening up new avenues for potentially being able control or prevent type 2 diabetes.

"We suspect this communication system between adipose tissue and liver may have evolved to help fat cells command the liver to supply the body with glucose in times of nutrient deprivation, said Hotamisligil. “However, when the engorged fat cells lose control over this signal in obesity, the blood levels of aP2 rise, glucose is poured into the bloodstream and cannot be cleared by other tissues. The result is high blood glucose levels and type 2 diabetes."

The researchers also identified a potential therapeutic role for a novel aP2 antibody that neutralises aP2 activity and corrects type 2 diabetes in mice.

"It was surprising to find that a critical hormone playing a pathological role in diabetes turned out to be the secreted form of aP2, which for decades has been considered a protein that resides inside the fat cells," said Hotamisligil.

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