Ceramide enhanced the hepatic glucagon response through regulation of CREB activity

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

“…Recent clinical studies have further demonstrated a substantial increase in both plasma and urinary ceramide levels in T2DM patients, suggesting ceramide could be used as a potential clinical evaluation index for T2DM ( Chew et al, 2019 ; Nehus et al, 2024 ). Additionally, the ceramide content in the serum of T2DM patients exhibited a positive correlation with blood glucose value, body weight, and total triglycerides ( Wang J. et al, 2023 ). Ceramide is known to stimulate fatty acids uptake.…”

“…In hepatocytes, glucagon enhances PP2A activation, with ceramide further supporting PP2A activation and dephosphorylation of transcriptional coactivator 2 (CRTC 2). CRTC 2 translocates into the nucleus and binds to CREB to form a transcriptional complex and induce its activity, consequently causing gluconeogenic gene transcription and diabetes ( Wang J. et al, 2023 ). The application of PP2A inhibitors proves effective in mitigating ceramide-induced inhibition on Akt/PKB, restoring insulin signaling ( Chavez and Summers, 2003 ; Stratford et al, 2004 ), and effectively facilitating CRTC 2 phosphorylation regulated by cAMP reactive element binding protein (CREB) in hepatocytes.…”

“…The application of PP2A inhibitors proves effective in mitigating ceramide-induced inhibition on Akt/PKB, restoring insulin signaling ( Chavez and Summers, 2003 ; Stratford et al, 2004 ), and effectively facilitating CRTC 2 phosphorylation regulated by cAMP reactive element binding protein (CREB) in hepatocytes. This, in turn, inhibits CRTC 2 in the cytosol, curbing hepatic gluconeogenesis ( Wang J. et al, 2023 ). In addition, ceramide activates PKC and the activated PKC phosphorylates Thr 34 on Akt, resulting in the recruitment of Akt to the cytoplasmic membrane, impairing insulin signaling ( Maceyka et al, 2012 ).…”