Role of Plasminogen Activator Inhibitor-1 in Glucocorticoid-Induced Diabetes and Osteopenia in Mice

Abstract

Long-term use of glucocorticoids (GCs) causes numerous adverse effects, including glucose/lipid abnormalities, osteoporosis, and muscle wasting. The pathogenic mechanism, however, is not completely understood. In this study, we used plasminogen activator inhibitor-1 (PAI-1)–deficient mice to explore the role of PAI-1 in GC-induced glucose/lipid abnormalities, osteoporosis, and muscle wasting. Corticosterone markedly increased the levels of circulating PAI-1 and the PAI-1 mRNA level in the white adipose tissue of wild-type mice. PAI-1 deficiency significantly reduced insulin resistance and glucose intolerance but not hyperlipidemia induced by GC. An in vitro experiment revealed that active PAI-1 treatment inhibits insulin-induced phosphorylation of Akt and glucose uptake in HepG2 hepatocytes. However, this was not observed in 3T3-L1 adipocytes and C2C12 myotubes, indicating that PAI-1 suppressed insulin signaling in hepatocytes. PAI-1 deficiency attenuated the GC-induced bone loss presumably via inhibition of apoptosis of osteoblasts. Moreover, the PAI-1 deficiency also protected from GC-induced muscle loss. In conclusion, the current study indicated that PAI-1 is involved in GC-induced glucose metabolism abnormality, osteopenia, and muscle wasting in mice. PAI-1 may be a novel therapeutic target to mitigate the adverse effects of GC.

Metabolic comorbidities in Cushing's syndrome

“…In mice, plasminogen activator inhibitor 1 (PAI1) expression was upregulated in white adipose tissue by corticosteroids, and transgenic PAI1 deficiency was able to counteract the negative effects of GCs on glucose metabolism, reducing insulin resistance (32).…”

“…Other factors have also been thought to be implicated in GC-associated myopathy, such as the GC effects on potassium and phosphate levels and mitochondrial function (209,222). A recent study showed that mice lacking PAI1 are protected from GC-induced muscle atrophy (32). In humans, however, the mechanism leading to muscle loss may not be exactly the same as in rodents, and the precise contribution of anti-anabolic and catabolic GC effects to myopathy needs to be clarified.…”

Aqueous extract of pomegranate seed attenuates glucocorticoid-induced bone loss and hypercalciuria in mice: A comparative study with alendronate

“…In vitro studies have revealed that DEX induces cytotoxicity and apoptotic cell death in osteoblastic cells and increases the life span of osteoclastic cells, and the apoptosis of osteoblasts is demonstrated by the decrease in the sub-G1 cell population (27,28). In vivo studies demonstrated that, in contrast to the non-treated rabbits or mice, the DEX-injected subjects exhibited the typical features of GIOP as shown by the measurement of the basic biomechanical parameters, including reductions in BMD, and the increased disconnections and separation of the trabecular bone network (29,30). It has been found that these pathological changes in bone metabolism correlate with disturbances of calcium homeostasis (31).…”

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

“…Since FOXO1 upregulation is associated with reduced insulin signaling in adipocytes treated with TNF-α [43] , a molecular feature similar to those caused by GCs, in vivo studies addressing this question might contribute for elucidation of the possible involvement of MKP-3 and FOXO1 in the GC-induced impairment of insulin signaling in the adipose tissue. Finally, recent studies demonstrated the involvement of two proteins -progranulin [44] and plasminogen activator inhibitor (PAI)-1 [45] -on glucose and lipid abnormalities caused by high-fat diet and GC, respectively, reinforcing the diversity and complexity of signals that may modulate peripheral insulin response.…”