Diabetes drug to correct metabolic abnormalities

Type 2 diabetes is a major public health problem that affects millions of people worldwide, so developing new drugs to help better treat its underlying causes is something of a priority. An international team of scientists has now developed a peptide known as PATAS, part of a new class of antidiabetic drugs, which can correct the metabolic abnormalities leading to type 2 diabetes and its associated comorbidities — including insulin resistance.

The prevalence of type 2 diabetes, which is characterised by high levels of glucose in the blood, has been increasing for decades due to population aging, inactivity and poor diet. Available drugs treat the consequences of type 2 diabetes by focusing mainly on lowering blood glucose, but they do not target the underlying biological mechanism that causes the disease. Furthermore, despite the need for new and more effective treatments, there have been no disruptive therapeutic innovations to reach market in over a decade.

This is the objective of the research led by Vincent Marion, from the French National Institute of Health and Medical Research (Inserm), and his team at the University of Strasbourg. In collaboration with the University of Birmingham and Monash University, the scientists developed a product called PATAS in a new class of diabetes drugs called “Adipeutics”. PATAS works by specifically targeting the adipocytes (fat cells), restoring glucose entry and thus correcting and re-establishing the metabolic physiology of the adipose tissue.

The role of adipocytes

In previous research, published in 2020, the research team had identified a new therapeutic target for type 2 diabetes when investigating an ultra-rare monogenic disease known as Alström syndrome. They showed that adipose tissue abnormalities caused by a dysfunctional protein called ALMS1 led to extremely severe insulin resistance associated with early-onset type 2 diabetes in people with Alström syndrome. In animal models, restoring the function of this protein within the adipocytes re-established blood glucose balance.

The researchers then went on to focus more closely on ALMS1 and how it interacts with other proteins within the adipocytes. In particular, they have shown that in the absence of insulin, ALMS1 binds to another protein called PKC alpha. The activation of insulin in the adipocytes induces the separation of ALMS1 and PKC alpha, resulting in glucose entry into cells. In people with diabetes, who are insulin-resistant, this link between the two proteins is maintained.

Drawing on this knowledge, the scientists developed the peptide PATAS, which works by breaking the interaction between ALMS1 and PKC alpha — thus restoring insulin signalling in the adipocytes. Their latest study, conducted on animal models and published in the journal Diabetes, confirms that PATAS restores glucose uptake in the adipocytes, resulting in the treatment of insulin resistance with beneficial effects on the whole body.

“Thanks to PATAS, the adipocytes that could no longer access glucose were once again able to absorb it and then metabolise it in order to synthesise and secrete lipids which are beneficial to the entire body,” Marion said. “These positive effects are visible in our animal models, with a marked improvement in insulin resistance. Other parameters and comorbidities are also improved, including better blood glucose control and decreased liver fibrosis and steatosis.”

The successful development of a new class of antidiabetic drugs could have significant implications for public health, not only to treat type 2 diabetes but also many other cardio-metabolic disorders in which dysfunctional adipocytes and insulin resistance are problematic. And with promising results in animals, the researchers plan on organising a clinical trial as soon as possible, in order to test PATAS in humans.

Image caption: Mouse visceral adipose tissue fluorescently labelled; nuclei coloured blue. Image courtesy Vincent Marion.

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