Mouse visceral adipose tissue fluorescently labeled with AdipoRed. Nuclei are stained blue. © Vincent Marion.

Type 2 diabetes is a major public health problem that affects millions of people worldwide. Developing new drugs to help better treat its underlying causes is therefore a research priority. In a new study coordinated by Inserm researcher Vincent Marion in collaboration with the University of Birmingham (UK), Monash University (Australia), and along with Alexander Fleming, former senior endocrinologist at the US Food and Drug Administration (FDA), the scientists have developed PATAS, a peptide that is part of a new class of antidiabetic drugs. PATAS can correct the metabolic abnormalities leading to type 2 diabetes and its associated comorbidities which include insulin resistance^[1]. PATAS works by specifically targeting the adipocytes (fat cells)^[2], restoring glucose entry and thus correcting and re-establishing the metabolic physiology of the adipose tissue. The teams hope to set up a clinical trial soon to test this new therapy. Their study has been published in the journal Diabetes.

Diabetes mellitus is a chronic condition that affects 537 million people worldwide, with the majority affected by type 2 diabetes. The prevalence of type 2 diabetes, which is characterized by high levels of glucose in the blood (see box), has been increasing for decades due to population aging, inactivity, and poor diet. The age of onset is also decreasing, and although the disease is considered to be an “adult disease”, it is now seen frequently in adolescents and children.

Available drugs treat the consequences of type 2 diabetes by focusing mainly on lowering blood glucose; they do not target the underlying biological mechanism that causes the disease.

And this is precisely the objective of the research led by Inserm researcher Vincent Marion and his team at the Medical Genetics Laboratory (Inserm/Université de Strasbourg). In a recent study in collaboration with the University of Birmingham and Monash University, the scientists have developed a product called PATAS in a new class of diabetes drugs called “Adipeutics” (for therapies that specifically target the adipocytes).

Their study, conducted on animal models, shows that this new therapy specifically restores glucose uptake in the adipocytes, resulting in the treatment of insulin resistance with beneficial effects on the whole body. This is made all the more promising by the fact that treating insulin resistance has the potential to address not only type 2 diabetes but a large array of serious medical conditions that result from this resistance.

The role of adipocytes

This study follows on from years of rigorous, in depth work carried out in the lab. In previous research, published in Diabetes in 2020, the scientists had identified a new therapeutic target for type 2 diabetes when investigating at an ultra-rare monogenic disease known as Alström syndrome.

The scientists had shown 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 teams 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 these two proteins 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 have developed the peptide PATAS, which works by breaking the interaction between ALMS1 and PKC alpha – thus restoring insulin signaling in the adipocytes.

In mouse models of diabetes, PATAS has been able to re-establish the normal physiology of the adipocytes by restoring glucose uptake. “Thanks to PATAS, the adipocytes that could no longer access glucose were once again able to absorb it and then metabolize it in order to synthesize and secrete lipids which are beneficial to the entire body. 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,” explains Vincent Marion.

These promising results in animals have paved the way for the researchers to organize a clinical trial as soon as possible, in order to test PATAS in humans. 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 very problematic.

In order to create value from these findings and facilitate the organization of such a trial, Vincent Marion has founded the start-up AdipoPharma SAS.

^[1] Insulin resistance is when cells in your muscles, fat, and liver do not respond well to the hormone insulin and can’t use glucose from the blood as their energy source. Insulin resistance is the basis of high blood fats, heart and vascular disorders, metabolic syndrome and type 2 diabetes

^[2] Adipose tissue is a set of cells known as adipocytes that store fats.

The effect of G60R mutation on CLDN-5 expression and localization in CLDN-null cells. © Matthew Campbell, Smurfit Institute of Genetics, Trinity College Dublin

Scientists at Trinity College Dublin and the Institute Imagine at Necker Hospital, Paris, announced a significant advance in our understanding of a very rare condition called alternating hemiplegia of childhood (AHC). This is a devastating condition that can lead to repeated paralysis that affects one side of the body or the other or sometimes both at once. It usually begins to affect children before 18 months of age and to date, only one causative gene has been identified.

Here, scientists in Dublin and Paris have now identified a second gene CLDN5 as being responsible for the condition in 2 unrelated cases of AHC in France. The protein product of this gene, claudin-5, is critical for maintaining the integrity of the blood-brain barrier (BBB). Intriguingly, the mutated form of the protein turns the barrier into a channel that is selective for negatively charged ions. In this regard, the ionic compositions of the brain are likely shifted in these children and this is a key driver of the condition.

“This finding was based on an amazing collaboration with Prof Arnold Munnich’s group at the Institute Imagine in Paris. The identity of these de novo mutations in unrelated children suggests that the barrier is turning into a channel. This is exciting on numerous levels as it is the first report of the BBB turning into a channel, but it also sheds light on the devastating pathology of AHC which may assist in clinical management of patients with this mutation” said Dr Matthew Campbell, Associate Professor at Trinity.

Importantly, the work has implications for our basic understanding of the junctional protein that forms the BBB. As this is the first report of the human BBB becoming a channel, there may be avenues for drug delivery that have never been explored. This will now form the basis of the next steps of the project.

Dr Yosuke Hashimoto, visiting researcher from the Japanese Society for the Promotion of Science (JSPS), and his equally contributing colleague Dr Karine Poirier from the Institute Imagine added: “This exciting project has shed light on a very rare condition affecting children. We are delighted that our work was able to quickly identify the causative mutation for the disease as well as progressing our understanding of the pathology of the disease.”

Commenting on the study, Prof Arnold Munnich from the Institute Imagine in Paris said “We are delighted this work has progressed so quickly and our groups have been able to work very closely to identify the cause of this condition. Studies like this will benefit families and clinicians immensely in the years to come”.

A multidisciplinary team of Geneticists, Neurologists and Radiologists from Ireland and France undertook the study.