Blog Layout

EPDR1, a novel human batokine regulating β cell metabolism and function

Hjelt Grant Holder 2022, Rodrigo Cataldo
Anja Schmidt-Christensen
Rodrigo Cataldo,
Hjelt Grant Holder 2022,
Lund University.

Background
The role of beta cells is to sense glucose and response by releasing insulin to maintain glucose homeostasis. Consequently, the loss of beta cell function is the main culprit of type 2 diabetes development.

Ependymin-related protein 1 (EPDR1) was recently identified as a protein released by the human brown adipose tissue, where it plays a role in regulating thermogenesis, a protective metabolic process that transform stored fat into heat. It was suggested that EPDR1 may act as a novel hormone regulating whole-body energy metabolism.
Apart of this, the biological role of EPDR1 is poorly known.
I have identified that human beta cells also produce EPDR1 protein and that its expression is upregulated in pancreatic islets from Type 2 diabetes vs. non diabetic donors and that its expression is associated to beta cell function.

Hypothesis
Based on the data obtained so far, I believe that EPDR1 expression in beta cells may increase in response to the metabolic stress caused by overfeeding in obese people to, in a compensatory fashion, restore glucose metabolism and maintain beta cell function.

Methods
I aim to apply a cutting-edge methodology, Metabolic Flux Analysis (MFA), which is based in fueling beta cells with labeled energy substrates and then quantify the rate of different metabolic pathways underlying insulin secretion. With this method we plan to elucidate the mechanism of action for EPDR1 in regulating beta cell function. 

I also plan to study animals that lack EPDR1, make them obese (to mimic metabolic stress in obese people) and test beta cell function (in vitro) and glucose tolerance (in vivo) to understand the role of EPDR1 in beta cell function and glucose homeostasis.  

Results
I have so far conducted some in vitro experiments and found that treatment of beta cells with EPDR1 protein increases insulin secretion whereas silencing EPDR1 expression reduces insulin secretion.
I have performed metabolomics experiments and found that silencing EPDR1 expression in beta cells alter the levels of glucose-derived metabolites in different relevant pathways associated to insulin secretion.

Conclusions
I have found that EPDR1 is required to maintain normal human beta cell function.
EDPR1 regulates glucose metabolism by increasing coupling of glycolysis and mitochondrial function in beta cells.

Importance
The proposed research project will help to elucidate the role of EPDR1 for beta cell function and glucose homeostasis and to deepen the knowledge of molecular mechanisms of EPDR1 to regulate beta cell metabolism and function.
We have also identified genetic variants associated to EPDR1 expression in human beta cells and function and this study will also explore the potential of these genetic variants to make advances of precision medicine in Type 2 diabetes.
Finally, if we confirm the positive effects of EPDR1 protein for human beta cell function and glucose homeostasis, EPDR1 could become a target to develop treatments for obese people to prevent progress to T2D.


Share by: