Novel Mechanism Identified to Modulate Glucagon Signaling

The peptide hormone glucagon is responsible for generating energy for the body via the release and breakdown of stored glucose and lipids from the liver. However, whether glucose and lipid energy sources can be activated independently was unknown until recently. Researchers at the Helmholtz Munich Institute for Diabetes and Cancer (IDC) and the German Center for Diabetes Research (DZD) revealed that depleting a specific liver protein allows distinct activation of glucose metabolism on intracellular membranes without affecting lipids.

The liver plays an essential role in maintaining balanced blood glucose levels. In type 2 diabetes, however, this pathway becomes overactivated and leads to excessive glucose production in the blood, called hyperglycemia. The modulation of this glucose production process has been a priority for researchers studying mechanisms of action and treatment for diabetes. 

Since glucagon not only controls glucose production but also mediates lipid breakdown, pharmacological inhibition of glucagon has been proven to be challenging. Notably, inhibiting glucagon function has the undesirable side effect of causing lipid accumulation in the liver. While many researchers have attempted to untether these two processes, the IDC team identified a novel method to disconnect these pathways.

The scientists were able to interfere with intracellular signaling pathways of glucagon’s receptors (Gcgr) with a Cy5-glucagon agonist. They found that the endosomal protein Vps37a uncouples glucose production from lipid usage of downstream glucagon signaling by altering intracellular receptor localization.  

These findings, published in the journal Cell Metabolism, demonstrate that altering the intracellular distribution of Gcgr regulates glucose production independently of its role in lipid metabolism. Their results also coincide with previous findings suggesting that simply changing the localization of a GPCR alters its signaling activity, insinuating that the endosomal membrane environment favors an active confirmation of Gcgr.

While the study retained some limitations, such as not addressing the cause and consequences of this reduction in circulating blood glucose levels without affecting fatty acid oxidation, the team wants to conduct more work to understand how potential targets, such as Vps37a and ESCRT-1 subcomplexes, affect different tissues in various physiological and disease conditions.

These results may help broaden the range of available therapies for type 2 diabetes with a novel, sophisticated method for using glucagon inhibition to effectively lower blood glucose levels without causing adverse lipid-related side effects.