promising avenues for personalized treatment · Inserm, science for health

At Cochin Institute (Department Insert 1016 / CNRS / Université Paris Cité), Ralf Jockers, Inserm research director and head of the “Functional Pharmacology and Physiopathology of Membrane Receptors” team, was interested in the consequences of mutations in a gene that codes for receptor A peptide says ” Glucagon-like”, GLP1R, a hormone involved in triggering the feeling of satiety.

In collaboration with French, British and Chinese research teams, he published in Nature Metabolism the results of a study in which he showed that these mutations have effects on metabolic properties such as the regulation of glucose and body weight, while also influencing the effectiveness of Agonists of GLP1R, which is clinically used to treat diabetic and/or obese patients.

The context

Glucagon-like peptide 1 (GLP1), a key hormone released primarily from the gastrointestinal tract in response to food intake, plays a central role in regulating insulin secretion and body weight. Its effect is exerted through activation of the receptor Glucagon-like peptide 1 (GLP1R), present in both pancreatic β-cells and brain.

GLP1R agonists such as liraglutide and semaglutide have emerged as essential tools in the treatment of type 2 diabetes (T2D) and obesity. But despite their use, the question remains unanswered to this day: What real significance do natural mutations of the GLP1R gene have in humans?

At the Cochin Institute, Ralf Jockers and his collaborators sought to highlight the connection between genetic variations in GLP1R and the metabolic properties associated with T2DM and obesity, as well as their impact on response to current treatments. Your goal? Adapt therapies to individual variations, paving the way for increased potential of personalized medicine in the field of metabolism.

The results

An in-depth functional genetic analysis was performed on 60 rare variants of the GLP1R gene. Of these variants, 56 showed significant effects on the GLP1R receptor, disrupting its function by causing abnormalities in its cell surface expression and altering the cyclic adenosine monophosphate (cAMP) pathway, an essential intracellular messenger. cAMP plays a crucial role in transmitting signals necessary to regulate various metabolic processes in cells.

These disorders have serious consequences, including disorders of insulin secretion. However, researchers have shown promising ways to correct these anomalies.

Two pharmacological approaches have proven successful:

the use of high concentrations of agonists that act as molecular stimulants;
the subtle combination of low concentrations of agonists and positive allosteric modulators (PAMs) that act as regulators and restore the correct balance in the cellular response.

On the other hand, mutations have been linked to loss-of-function (LoF) in GLP1R, discovered in 200,000 participants of the UK Biobank, a large genetics and health database that collects details on the genetics, lifestyle and health of hundreds of thousands of participants Glucose regulation and increased adiposity. It appears that GLP1R plays an important role in orchestrating these metabolic processes.

This consortium also observed that LoF mutations in the β-arrestin signaling pathway could actually improve certain metabolic properties. This pathway acts as a brake on GLP1R signaling. It was found that by obstructing this pathway, the regulation of insulin secretion could be improved.

Perspectives

This study suggests that loss-of-function (LoF) mutations of the GLP1R receptor, particularly those resulting in defective cell surface GLP1R expression or impaired cAMP activation, are associated with defective insulin secretion in vitro as well as disorders of insulin secretionHomeostasis Glucose and increased adiposity in UK Biobank participants.

These results are of great importance for personalized medicine and offer therapeutic possibilities for people with genetic variants associated with risk. Treatments targeting the GLP1R receptor, including its homologue GIPR (GLP1R receptor), glucose-dependent insulinotropic agent Polypeptide), such as GLP1R/GIPR agonists, are emerging as crucial options for regulating blood glucose and metabolism.

In parallel, the use of GLP1R-specific positive allosteric modulators (PAMs) offers a promising approach by increasing GLP1R receptor activity, thereby enabling more efficient modulation of metabolism.

Research into the intracellular Gs/cAMP signaling pathway is also important. When the GLP1R receptor is activated, it stimulates the Gs protein (protein). G-stimulator), which triggers the production of cAMP. Drugs that target this pathway rather than the β-arrestin pathway could represent a major advance in metabolic regulation.

The effects of defective GLP1R expression on the cell surface suggest that pharmacological chaperones, molecules known to facilitate adequate protein export to the cell surface, may be of therapeutic importance to mutation carriers.

These discoveries pave the way for diversifying therapeutic options targeting GLP1R, benefiting carriers of LoF mutations as well as obese and diabetic patients who are resistant to current treatments or face serious side effects. In conclusion, this study offers diverse perspectives to address the specific treatment needs of each individual.