The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside

Abstract

Tacrolimus (TAC), the mainstay of maintenance immunosuppressive agents, plays a crucial role in new‐onset diabetes after transplant (NODAT). Previous studies investigating the diabetogenic effects of TAC have focused on the β cells of islets. In this study, we found that TAC contributed to NODAT through directly affecting hepatic metabolic homeostasis. In mice, TAC‐induced hypoglycemia rather than hyperglycemia during starvation via suppressing gluconeogenetic genes, suggesting the limitation of fasting blood glucose in the diagnosis of NODAT. In addition, TAC caused hepatic insulin resistance and triglyceride accumulation through insulin receptor substrate (IRS)2/AKT and sterol regulatory element binding protein (SREBP1) signaling, respectively. Furthermore, we found a pivotal role of CREB‐regulated transcription coactivator 2 (CRTC2) in TAC‐induced metabolic disorders. The restoration of hepatic CRTC2 alleviated the metabolic disorders through its downstream molecules (eg, PCK1, IRS2, and SREBP1). Consistent with the findings from bench, low CRTC2 expression in graft hepatocytes was an independent risk factor for NODAT (odds ratio = 2.692, P = .023, n = 135). Integrating grafts’ CRTC2 score into the clinical model could significantly increase the predictive capacity (areas under the receiver operating characteristic curve: 0.71 vs 0.79, P = .048). Taken together, in addition to its impact on pancreatic cells, TAC induces “hematogenous diabetes” via CRTC2 signaling. Liver‐targeted management may be of help to prevent or heal TAC‐associated diabetes.

A multi-omics study to investigate tacrolimus nephrotoxicity mechanisms

“…In fact, tacrolimus diabetogenic effect is probably mediated by its impact on insulin secretion and activity and not on glucose catabolism. In addition, a study conducted in mice treated with tacrolimus showed decreased glycemia after 16h of fasting as compared to controls, confirming that tacrolimus affects gluconeogenesis (Ling et al, 2020). All these findings and arguments converge to highlight the effect of tacrolimus on gluconeogenesis.…”

“…In fact, PKC-1 -/- mice showed a tenfold increase in malate level in the liver as compared to controls (Hakimi et al, 2005). In addition, a study performed on a hepatic cell line and in mice showed that tacrolimus decreased the hepatic expression of PCK-1 (Ling et al, 2020). This effect was also seen in a primary culture of human β-pancreatic cells exposed to tacrolimus (Kolic et al, 2020).…”

Decoding the single-cell landscape and intercellular crosstalk in the transplanted liver: a 4-dimension mouse model

“…Our previous studies in both large human cohorts [45, 46] and mice models [19] demonstrated an imbalanced hepatic metabolic homeostasis after LT. This study not only proved that hepatocytes showed a metabolic reprogram after LT including insulin resistance, glucose and lipid metabolic homeostasis, but also revealed a comprehensive interplay between macrophage and hepatocytes in the transplanted liver.…”

“…Immunohistochemistry was performed as we described previously [19]. Liver specimens (4μm) were stained with hematoxylin and eosin (H&E).…”

The role of transcription factor 7‐like 2 in metabolic disorders

“…CREB phosphorylation can be stimulated by glucagon, and it then regulates the expression of G6Pase and PEPCK 147 . CRTC2 is a coactivator of CREB, and a dys‐regulation in its expression can cause a glucose homoeostasis imbalance 148 . Finally, FOXO1 is also involved in the regulation of G6Pase and PEPCK 149 .…”