Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.

In Saccharomyces cerevisiae, double-strand breaks (DSBs) activate DNA checkpoint pathways that trigger several responses including a strong G 2 /M arrest. We have previously provided evidence that the phosphatases Ptc2 and Ptc3 of the protein phosphatase 2C type are required for DNA checkpoint inactivation after a DSB and probably dephosphorylate the checkpoint kinase Rad53. In this article we have investigated further the interactions between Ptc2 and Rad53. We showed that forkhead-associated domain 1 (FHA1) of Rad53 interacts with a specific threonine of Ptc2, T376, located outside its catalytic domain in a TXXD motif which constitutes an optimal FHA1 binding sequence in vitro. Mutating T376 abolishes Ptc2 interaction with the Rad53 FHA1 domain and results in adaptation and recovery defects following a DSB. We found that Ckb1 and Ckb2, the regulatory subunits of the protein kinase CK2, are necessary for the in vivo interaction between Ptc2 and the Rad53 FHA1 domain, that Ckb1 binds Ptc2 in vitro and that ckb1⌬ and ckb2⌬ mutants are defective in adaptation and recovery after a DSB. Our data thus strongly suggest that CK2 is the kinase responsible for the in vivo phosphorylation of Ptc2 T376.The DNA checkpoint is a surveillance mechanism that detects DNA lesions or replication blocks and coordinates various responses such as cell cycle arrests and transcriptional or posttranscriptional modifications. This mechanism is present in all eukaryotes and has been particularly analyzed in the yeast Saccharomyces cerevisiae, where it was originally identified (14, 53). In S. cerevisiae, activation of the DNA checkpoint by DNA lesions depends essentially on two sets of proteins, Rad24 and the PCNA-like trimer Rad17-Mec3-Ddc1, on the one hand, and the ATR homolog, the phosphatidylinositol 3-kinase-like Mec1 (in complex with an auxiliary subunit Ddc2), on the other hand (reviewed in references 28 and 58). Both the Rad17-Mec3-Ddc1 and the Mec1-Ddc2 complexes have been shown to be simultaneously and independently recruited to a double-strand break (DSB) artificially induced by the HO endonuclease (15,29). Once activated, Mec1 induces the phosphorylation and the activation of two central transducers, the Rad53 and Chk1 kinases, which subsequently phosphorylate downstream effectors. The phosphorylation of Rad53 and Chk1 also depends on so-called "adaptors," Rad9 in the case of DNA damage and Mrc1 in the case of replication blocks and DNA lesions during S phase (for a review on Rad53 activation, see reference 33).Rad53 plays a central part in S. cerevisiae DNA checkpoint: it controls the majority of the DNA damage responses and rad53⌬ cells are strongly hypersensitive to all genotoxic stresses. Rad53 is the founding member of the conserved family of FHA (forkhead associated) domain-containing checkpoint kinases, which also includes mammalian Chk2 and Schizosaccharomyces pombe Cds1. It contains two FHA domains, FHA1 and FHA2, flanking the protein catalytic domain. FHA domains are protein-protein interaction domains that specifica...