Harvard team disables newly discovered hormone to reverse diabetes in mice

Harvard team disables newly di...
Artist's impression of insulin interacting with the surface of cells
Artist's impression of insulin interacting with the surface of cells
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Artist's impression of insulin interacting with the surface of cells
Artist's impression of insulin interacting with the surface of cells

Scientists at Harvard University have made a breakthrough that implicates a newly discovered hormone in the onset of diabetes, and shown how it can be targeted to reverse the effects of the disease. The results of the experiments in mice suggest the same mechanisms are at play in humans, with the authors presenting the hormone as a promising new therapeutic target.

The research centers on the way energy is regulated in the body and the different hormones that play a part in this process. Insulin is a well-known example of this, helping the body draw glucose from the blood and use if for fuel. Leptin is another, produced by fat cells and signaling to the brain when we've had enough to eat.

The hormone at the heart of this latest discovery works a little differently, in that it isn't a single molecule with a single receptor like those above, but is actually made up of a few different building blocks. It all begins with a protein called FAB4 that was discovered more than a decade ago, which is secreted by fat cells into the blood stream as a typical response to starvation.

Studies since have uncovered strong correlations between circulating FAB4 and metabolic conditions such as diabetes, obesity and cardiovascular disease. The details of such relationships have remained an unknown, but the Harvard team behind this new study have now filled in some of the important blanks.

The scientists were able to show that as FAB4 enters the bloodstream, it binds with the enzymes adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to form a protein complex they've called fabkin. In doing so, it alters the activity of these enzymes and, in turn, changes levels of the molecules ATP and ADP, which play key roles in the metabolism of living cells.

Neighboring cells sense these changes via receptors on their surface and undergo changes of their own in response. The researchers found victims of this process were beta cells in the pancreas that produce insulin, which are lacking or dysfunctional in people with type 1 and 2 diabetes. Through this chain of events, the scientists found fabkin to be a driving force behind the development of the disease.

“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes (fat cells) to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” says senior author Gökhan S. Hotamisligil. “We now have identified fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”

Taking things a little further, the scientists then deployed an antibody to neutralize fabkin in mice at risk of diabetes, and found that it preserved the beta cells and prevented the animals from developing both type 1 and type 2 diabetes. Administering the antibody to obese, diabetic mice actually returned them to a healthy state.

Because the study showed levels of fabkin to be abnormally high in mice and humans with type 1 or type 2 diabetes, the scientists believe the newly discovered hormone plays a similar role in people. Therefore, they regard the hormone as a highly promising target in the development of new therapies for the disease.

“The discovery of fabkin required us to take a step back and reconsider our fundamental understanding of how hormones work,” says lead author Kacey Prentice, research associate in the Sabri Ülker Center and Department of Molecular Metabolism. “I am extremely excited to find a new hormone, but even more so about seeing the long-term implications of this discovery.”

The research was published in the journal Nature

Source: Harvard University via EurekAlert

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