Proteins named after a Greek goddess could lead to new diabetes drugs

by Barbara Hewitt on February 1, 2018

Proteins named after a Greek goddess who spun the thread of life could help researchers develop future treatments for diabetes, new research has found.

It is already known that Klotho proteins which are involved in the ageing process can affect insulin sensitivity which is important when it comes to trying to prevent or reduce the risk of type 2 diabetes.

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In Greek mythology Klotho spun the thread of life and when cut it signalled it was time for someone to die. The protein, named after her, is associated with longevity and metabolism in the human body.

Now scientists at Yale University in the United States have looked at two specific proteins in the Klotho family, alpha and beta, which bind to hormones known as fibroblast growth factor (FGFs).

The researchers had already found the three dimensional structure of one of these proteins, beta-Klotho, illuminating its intricate mechanism and therapeutic potential and they now believe that both have important implications for a variety of diseases including diabetes and obesity which is associated with type 2 diabetes.

The Klotho family of two receptor proteins are located on the surface of cells of specific tissues. The proteins bind to the FGFs that regulate critical metabolic processes in the liver, kidneys, and brain.

To understand how beta-Klotho works, the research team used X-ray crystallography, a technique that provides high resolution, three dimensional views of these proteins.

They found that beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced upon starvation. When bound to beta-Klotho, FGF21 stimulates insulin sensitivity and glucose metabolism, causing weight loss.

They believe that this new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as type 2 diabetes in obese patients.

‘Like insulin, FGF21 stimulates metabolism including glucose uptake. In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21,’ said Joseph Schlessinger, senior author and chair of pharmacology at Yale School of Medicine.

The authors also found a new variant of FGF21 that has 10 times higher potency and cellular activity and evidence of how a structurally related enzyme, glycosidase, which breaks down sugars, evolved into a receptor for a hormone that lowers blood sugar.

Having untangled the structure of beta-Klotho, Schlessinger and his colleagues will now explore potential therapies. This could lead to the development of drugs that can target diabetes and obesity.

‘The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward. More studies are already in the pipeline,’ Schlessinger said.


The opinions expressed in this article do not necessarily reflect the views of the DiabetesForum.com Community and should not be interpreted as medical advice. Please see your doctor before making any changes to your diabetes management plan.

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