Opioids and insulin secretion: a new avenue to fight type 2 diabetes

Project Information

OpiO

Grant agreement ID: 101043671

DOI

10.3030/101043671

EC signature date 8 June 2022

Start date 1 October 2022

End date 30 September 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 997 915,00

EU contribution

€ 1 997 915,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - OpiO (Opioids and insulin secretion: a new avenue to fight type 2 diabetes)

Reporting period: 2022-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

Type 2 diabetes (T2D) and obesity are major health issues, causing illness and death worldwide. Despite many efforts, we still don’t fully understand how these diseases work, which has made it hard to develop better treatments. T2D and obesity are complex diseases influenced by many genes. While large genetic studies have found hundreds of genes related to metabolism, these findings haven’t yet led to new treatments. However, research on rare genetic mutations has been successful in helping create or repurpose drugs.

OπO explores a forgotten link between opioid use and metabolic issues like diabetes. Opioids affect the body through specific receptors, including the delta opioid receptor (DOP). My initial research suggests that DOP could be a key connection between opioids and metabolism, potentially affecting insulin production from pancreatic cells. This makes DOP an exciting possible target for T2D treatment.

The OπO project involves four main steps: first, studying the role of DOP and opioid signals in pancreas cells that control insulin; and then examining how opioids affect the whole body’s metabolism. We’ll use advanced methods like testing in animal models, detailed pancreas analysis, drug testing, and genetic studies in people. The aim is to gain insights that could lead to new, effective treatments for T2D.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Recent advancements of OpiO have provided significant insights into the genetic factors underlying type 2 diabetes (T2D), shedding light on potential therapeutic targets and personalized medicine approaches.

Delta Opioid Receptor (DOP) and Type 2 Diabetes
We have uncovered the role of the delta opioid receptor (DOP), encoded by the OPRD1 gene, in metabolic health. Genetic analysis revealed that certain variations in this gene influence body fat levels and the risk of T2D. Loss-of-function variants are linked to higher fat levels but lower diabetes risk, while gain-of-function variants show the opposite. Importantly, experiments demonstrated that blocking DOP activity enhances insulin secretion in pancreatic cells, positioning DOP as a promising target for T2D treatment. These results were published in 2024 in Nature Communcaitions.

A New Category: Oligogenic Forms of Type 2 Diabetes (including due to variants in OPRD1)
Traditional views classified T2D as either monogenic (caused by mutations in a single gene) or polygenic (involving many small genetic contributions). However, recent work suggests the existence of "oligogenic" T2D, where a small number of key genes play a crucial role. This new perspective bridges the gap between the two categories, offering deeper insights into T2D's molecular mechanisms and potential drug targets. This new category includes the rare variants included in OPRD1 gene.

Expanding the Genetic Landscape
Additional research beyond the OPRD1 gene study (using the exact same strategy) has identified several other genes linked to T2D and obesity, reinforcing the oligogenic hypothesis. These include:

POMC: A gene impacting appetite regulation (Genetics in Medicine, 2023).
DYRK1B: Associated with obesity and metabolic syndrome (Diabetes Care, 2024).
GLIS3: Involved in pancreatic function and insulin production (Diabetologia, 2023).
Together, these discoveries are paving the way for precision medicine, enabling treatments tailored to individual genetic profiles and opening new doors for managing metabolic diseases.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our recent publication in Nature Communications (Meulebrouck et al.) marks a major milestone: it demonstrates the critical role of the delta opioid receptor (DOP) in regulating insulin secretion from pancreatic beta cells. This finding validates the core hypothesis of my ERC-funded project, OpiO. While the role of another key gene, POMC, has yet to be confirmed, its potential as a groundbreaking discovery remains significant.

Additionally, the OPRD1 gene, which encodes the delta opioid receptor, has been identified as a novel contributor to oligogenic forms of type 2 diabetes (T2D). This builds on my earlier work, including the discovery of MTNR1B (encoding the melatonin receptor 1B) as the first gene linked to oligogenic T2D, published in Nature Genetics in 2012. The identification of OPRD1 continues this trajectory of uncovering genes that not only enhance our understanding of T2D but also serve as promising therapeutic targets for precision medicine.