CDF15 cytokine a promising therapeutic target against type 2 diabetes

CDF15 cytokine a promising therapeutic target against type 2 diabetes

Researchers have conducted a review of growth differentiation factor 15 (GDF15) – a protein expressed under physiological stress conditions – and its potential implications for the treatment of type 2 diabetes.

It was chaired by Professor Manuel Vázquez-Carrera from the Faculty of Pharmacy and Food Sciences and the Institute of Biomedicine (IBUB) at the University of Barcelona.

The study, published in the journal Trends in Endocrinology and Metabolism, summarizes the latest research studies on the functioning of this cytokine, consolidating it as a potential therapeutic target against this disease.

“This review summarizes the latest novelty in the metabolic effects of GDF15 in the context of type 2 diabetes, which represents an important twist on what we previously knew. The results in animal models are particularly encouraging and show that GDF15-based therapies show promise for the treatment of this disease, although we need further human clinical trials to confirm this,” said Manuel Vázquez-Carrera, also a researcher at the Sant Joan Research Institute de Déu (IRSJD) and at the Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM).

Beneficial effects on metabolism

Type 2 diabetes is a complex metabolic disease that is mainly characterized by an excessive amount of glucose in the blood because the body is unable to produce insulin or uses it incorrectly. In situations of intracellular organelle stress, such as those caused by these and other diseases, cells secrete stress-sensitive cytokines such as GDF15, which activate mechanisms to counteract processes such as inflammation or insulin resistance.

Recent studies have shown that these metabolic benefits are produced through activation of the GFRAL receptor in the brain. Once activated, uptake is reduced and subsequent weight loss occurs, which would reduce obesity and improve comorbidities like type 2 diabetes.

However, new evidence gathered in this review indicates that GDF15 may have effects mediated by other peripheral receptors that help improve metabolic diseases.

“Previously, GDF15 effects were thought to be mediated exclusively through this central GFRAL receptor, whose expression is restricted to the neurons in the postrema region and the nucleus of the solitary tract, areas of the brain involved in hunger control and regulation of body weight,” said Vázquez-Carrera.

“Now it has been shown that GDF15 has beneficial effects such as increasing thermogenesis, lipid catabolism and mitochondrial oxidative phosphorylation independent of changes in dietary intake, suggesting that GDF15 may also exert its effects through receptors other than GFRAL and independently of it.” the reduction of hunger.”

According to the researchers, the discovery of the potential peripheral receptors responsible for the metabolic effects of GDF15 may help to better understand how this stress cytokine works and facilitate its pharmacological modulation.

alternative way

Vázquez-Carrera said his team made important advances in how GDF15 works. In a previous study, they found that this cytokine activates AMPK kinase, which regulates many processes related to cellular energy metabolism, such as increasing glucose uptake and oxidation of fatty acids, increasing mitochondrial oxidation capacity, and improving insulin sensitivity. This activation occurs independently of the GFRAL receptor in the brain, demonstrating an alternative pathway of GDF15-regulated energy metabolism.

“This kinase is an important regulator of metabolism and a fundamental therapeutic target for the treatment of type 2 diabetes because metformin, the drug of first choice for this disease, activates AMPK. “These results seem to indicate that part of the antidiabetic effect of GDF15 may be mediated through activation of AMPK,” he added.

New therapeutic challenges

The function of GDF15 as an appetite suppressant and regulator of energy metabolism has opened the door to the pharmacological administration of GDF15 for the treatment of type 2 diabetes.

However, the researchers warn that the pharmacokinetic and physicochemical properties of GDF15 pose several challenges for its development as a drug, such as the short average lifespan when administered subcutaneously or some side effects.

These obstacles have led to the development of GDF15 analogues, ie structurally similar chemical compounds aimed at improving the efficacy and pharmacokinetics of GDF15 for the treatment of diabetes.

The researchers said that some of these GDF15 analogues have already entered clinical trials.

Another potential therapeutic strategy has emerged from the recent discovery of the action of MT1-MMP, a type of protein capable of suppressing the effect of GDF15 on obesity-related appetite.

The researchers said this discovery opens the door to developing MT1-MMP inhibitors to potentiate the GDF15-GFRAL pathway and its appetite-suppressing effects. Therefore, future steps will aim to determine the efficacy and safety of GDF15 or possible analogues or inducers of this cytokine.

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