Towards a new class of drugs to treat type 2 diabetes

Type 2 diabetes is a major public health problem affecting millions of people worldwide. Developing new drugs that better treat the underlying causes of the disease is therefore a research priority. In a new study coordinated by Inserm researcher Vincent Marion at the Medical Genetics Laboratory (Inserm/University of Strasbourg), in collaboration with the University of Birmingham (United Kingdom), Monash University (Australia), and Alexander Fleming, former director of the Diabetes Division of the U.S. Food and Drug Administration (FDA), scientists have designed a new product called PATAS, in a new therapeutic class of anti-diabetics. This drug has the particularity of treating the very origin of type 2 diabetes and associated comorbidities, notably insulin resistance[1]. 1] PATAS specifically targets adipocytes, restoring glucose uptake and thus restoring the metabolic physiology of adipose tissue. The teams wish to set up a clinical trial to test this new therapeutic approach. The study is published in the journal Diabetes.

Diabetes is a chronic disease that affects 537 million people worldwide, the majority of whom are affected by type 2 diabetes. The prevalence of this pathology, characterized by high blood glucose levels (see box), has been increasing in recent years due to an aging population but also to sedentary lifestyles and poor eating habits. Type 2 diabetes is also occurring earlier and earlier.

Currently, all available drugs treat the consequences of type 2 diabetes by focusing primarily on glycemic control but do not target the underlying biological mechanism that causes the disease.

While there is a need to develop new and more effective treatments, no breakthrough therapeutic innovation has reached the market for over a decade.

This is the subject of work led by Inserm researcher Vincent Marion and his team at the Medical Genetics Laboratory (Inserm/University of Strasbourg). In a recent study conducted in collaboration with the University of Birmingham and Monash University, the scientists developed a product called PATAS in a new class of anti-diabetic drugs called “Adipeutics” (for ‘therapeutics specifically targeting the adipocyte’).

Their study, conducted in animal models, indicates that this new therapy specifically restores glucose uptake in the diseased adipocyte, thereby treating insulin resistance, with beneficial effects on the whole body.

The role of adipocytes

This study follows previous work by the team which identified a new therapeutic target for type 2 diabetes, by focusing on an ultra-rare monogenic disease, Alström syndrome.

The scientists had indeed demonstrated that abnormalities in adipose tissue[1] caused by the loss of function of a protein called ALMS1 led to extremely severe insulin resistance associated with early type 2 diabetes in people with Alström syndrome. Moreover, in animals, restoring the function of this protein only in adipocytes restored glycemic balance.

To go further, the teams took a closer look at this ALMS1 protein and how it interacts with other proteins in adipocytes. In particular, they showed that in the absence of insulin, the ALMS1 protein binds to another protein called PKC alpha. Conversely, the activation of insulin in the adipocyte induces the separation of these two proteins, resulting in the absorption of glucose. In diabetics, who are insulin resistant, this link between the two proteins is maintained.

Based on this knowledge, scientists have developed the PATAS peptide, which breaks the interaction between ALMS1 and PKC alpha and thus restores insulin signaling in the diseased adipocyte.

In diabetic mouse models, PATAS was able to restore normal adipocyte physiology by restoring glucose uptake. “With PATAS, adipocytes that had lost access to glucose are once again able to absorb glucose and then metabolize it to synthesize and secrete lipids that benefit the entire body while absorbing the extremely toxic non-esterified fatty acids. The effects are visible in animals, with a clear improvement in insulin resistance, and a whole host of other parameters and comorbidities, including better glycemic regulation, a reduction in steatosis and liver fibrosis,” explains Vincent Marion.

These promising results in animals allow the researchers to consider organizing a clinical trial soon to test PATAS in humans.

To valorize these results and facilitate the organization of such a trial, Vincent Marion has also founded the startup AdipoPharma SAS.