COVID-19-related hyperglycemia is associated with infection of hepatocytes and stimulation of gluconeogenesis.

Occurrence of hyperglycemia upon infection is associated with worse clinical outcome in COVID-19 patients. However, it is still unknown whether SARS-CoV-2 directly triggers hyperglycemia. Herein, we interrogated whether and how SARS-CoV-2 causes hyperglycemia by infecting hepatocytes and increasing glucose production. We performed a retrospective cohort study including patients that were admitted at a hospital with suspicion of COVID-19. Clinical and laboratory data were collected from the chart records and daily blood glucose values were analyzed to test the hypothesis on whether COVID-19 was independently associated with hyperglycemia. Blood glucose was collected from a subgroup of nondiabetic patients to assess pancreatic hormones. Postmortem liver biopsies were collected to assess the presence of SARS-CoV-2 and its transporters in hepatocytes. In human hepatocytes, we studied the mechanistic bases of SARS-CoV-2 entrance and its gluconeogenic effect. SARS-CoV-2 infection was independently associated with hyperglycemia, regardless of diabetic history and beta cell function. We detected replicating viruses in human hepatocytes from postmortem liver biopsies and in primary hepatocytes. We found that SARS-CoV-2 variants infected human hepatocytes in vitro with different susceptibility. SARS-CoV-2 infection in hepatocytes yields the release of new infectious viral particles, though not causing cell damage. We showed that infected hepatocytes increase glucose production and this is associated with induction of PEPCK activity. Furthermore, our results demonstrate that SARS-CoV-2 entry in hepatocytes occurs partially through ACE2- and GRP78-dependent mechanisms. SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK-dependent gluconeogenic effect in these cells that potentially is a key cause of hyperglycemia in infected patients.

Exploiting oxidized lipids and the lipid-binding GPCRs against cardiometabolic diseases.

Lipids govern vital cellular processes and drive physiological changes in response to different pathological or environmental cues. Lipid species can be roughly divided into structural and signalling lipids. The former is essential for membrane composition, while the latter are usually oxidized lipids. These mediators provide beneficial effects against cardiometabolic diseases (CMDs), including fatty-liver diseases, atherosclerosis, thrombosis, obesity, and Type 2 diabetes. For instance, several oxylipins were recently found to improve glucose homeostasis, increase insulin secretion, and inhibit platelet aggregation, while specialized pro-resolving mediators (SPMs) are able to ameliorate CMD by shaping the immune system. These lipids act mainly by stimulating GPCRs. In this review, we provide an updated and comprehensive overview of the current state of the literature on signalling lipids in the context of CMD. We also highlight the network encompassing the lipid-modifying enzymes and the lipid-binding GPCRs, as well as their interactions in health and disease.