CiMUS-USC researchers discover a key mechanism in the regulation of hepatic glucose production
• It is the so-called neddylation, studied until now in other pathological contexts such as cancer or hepatic fibrosis, but its functionality in this field is unknown
• The finding, which was published in the prestigious scientific journal Cell Metabolism, is essential in the approach to diabetes as it opens the door to new therapeutic approaches
Maintaining blood glucose (sugar) levels requires a set of coordinated systems in response to food availability or scarcity. Thus, during fasting, glucose is produced to prevent an excessive drop (hypoglycaemia), while after meals, glucose production is inhibited to prevent its uncontrolled excess (hyperglycaemia). The liver plays a key role in this process, as it is the body's main glucose producer. Now, the Molecular Metabolism group, led by Rubén Nogueiras at the CiMUS-USC, has just discovered a new essential mechanism in the regulation of hepatic glucose production: neddylation. The work, which has just been published in the most important scientific journal in this field, Cell Metabolism, paves the way for novel therapeutic approaches to diabetes, which is ranked as the seventh largest cause of death worldwide, according to the World Health Organization (WHO).
The study, coordinated from the CiMUS-USC by María Jesús González Rellán and Uxía Fernández Paz as first authors, also has the collaboration of different research groups from the singular centre of the USC, the CIBEROBN, the Clínica Universidad de Navarra, the CIC Biogune and the University of Seville, as well as international groups from Germany, Switzerland and France.
Neddylation and diabetes
The necessary regulation of the liver's production of glucose does not work properly in people with diabetes, a disease in which the body either does not produce enough insulin (type 1 diabetes) or cannot properly use the insulin it produces (type 2 diabetes), raising blood sugar levels, and causing serious health problems such as heart disease, kidney disease, high blood pressure, etc.
In molecular biology, post-translational modifications are chemicals that are added to proteins to change their properties, such as their activity, cellular localisation, or the ability to interact with other proteins. "Neddylation is one such post-translational modification, which involves adding a small protein called NEDD8 to target proteins. Unlike other molecular mechanisms that have been studied for many years and are very well defined, neddylation and its functions are still largely unknown. Specifically, its functions had been studied in certain pathological contexts, such as in cancer and liver fibrosis, where this post-translational modification stabilised proteins that favoured the progress of the disease," explains CiMUS researcher María Jesús González Rellán, first author of the article.
"In our study, adds González Rellán, "neddylation is described as an essential mechanism for regulating hepatic glucose production during fasting and after food intake. Specifically, during fasting, liver levels of the proteins NEDD8 and NAE1 (the enzyme responsible for neddylation) increase dramatically, allowing the liver to produce glucose.
As for how this effect is achieved, this study "describes for the first time that neddylation regulates the activity of phosphoenolpyruvate carboxykinase 1 (PCK1), one of the most important proteins in the process of glucose production by the liver, and which until now had not been attributed any type of modification as a determinant in regulating its activity," co-first author Uxía Fernández Paz says.
Other therapeutic options
Finally, the study also shows that neddylation levels are increased in the liver of type 2 diabetes patients. This represents a breakthrough in the study of the disease, providing a completely new and unexpected insight into how glucose production is regulated in the liver, and offering a tool to control and reduce PCK1 activity and, therefore, the high glucose levels characteristic of diabetic patients.