They identify the PKD2 protein as a modulator of hepatic insulin sensitivity in male mice.
ALICANTE. Investigationl CIBER (CIBERDEM) at the Sols-Morreale Institute of Biomedical Research (IIBM), mixed centerSupreme Council of Scientific Research (CSIC) and Autonomous University of Madrid (UAM), shows howProtein kinase D2 (PKD2) modulates insulin sensitivity in a preclinical model of obesity with metabolic fatty liver disease.
The work that was led Patricia Rada and Angela Martinez Valverde CIBER Division of Diabetes and Related Metabolic Diseases, also collaborated with other CIBER groups led by Tare you Iglesias (CIBERNED) and CArmelo García-Monzón and Patricia Azpichueta (CIBEREHD).
According to Patricia Rada, the first signatory of this study, it shows that “overexpression of hepatic PKD2 in mice resulted in mild dysregulation of glucose and decreased insulin signaling in the liver. In contrast, deficiency of “PKD2 in hepatocytes” in vivo resulted in improved glucose tolerance, as well as increased peripheral insulin tolerance and improved hepatic insulin signaling compared with control mice.”
At the molecular level, the study, published in the journal Molecular Metabolism, also shows that there is a connection between PKD2 and IRS1 (insulin receptor substrate 1), a key protein in the insulin signaling pathway.
“Our results indicate that PKD2 modulates the activation state of IRS1 such that its deficiency causes a decrease in inhibitory phosphorylation of IRS1, promoting its activation in the presence of insulin,” says Martinez Valverde, principal investigator of the CIBERDEM group at IIBM and co-coordinator of the study.
It is important to emphasize, as Elena Carceller-Lopez, co-author of the paper and a postdoctoral fellow at the IIBM, notes, that “this PKD2-mediated modulation of insulin sensitivity appears only in obese male mice and not in female mice.” “A possible explanation is that we noticed that PKD2 is activated in obese mice only in male mice, but not in female mice.”
To complete this study, in collaboration with the groups of Antonia García (CEMBIO, San Pablo, CEU) and Patricia Azpichueta (CIBEREHD and University of the Basque Country).
These results indicated that although mice exhibit a similar degree of steatosis regardless of PKD2, PKD2 deficiency in hepatocytes causes remodeling of lipid fluxes. “It is therefore tempting to speculate that in PKD2-deficient mice fed a high-fat diet, lipid remodeling may be beneficial in the long term and may delay progression to the more severe stage of MASLD,” Rada concludes.
In conclusion, this study identifies PKD2 as a negative modulator of insulin signaling in hepatocytes and suggests that modulation of PKD2 in the liver may be an effective therapeutic strategy for improving insulin resistance associated with metabolic liver diseases and obesity.