PIK3R1 (also known as p85α) is a regulatory subunit of phosphoinositide 3-kinases (PI3Ks). PI3K, a heterodimer of a regulatory subunit and a catalytic subunit, phosphorylates phosphatidylinositol into secondary signaling molecules involved in regulating metabolic homeostasis. PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3), which recruits protein kinase AKT to the inner leaflet of the cell membrane to be activated and to participate in various metabolic functions. PIK3R1 stabilizes and inhibits p110 catalytic activity and serves as an adaptor to interact with insulin receptor substrate (IRS) proteins and growth factor receptors. Thus, mutations in PIK3R1 or altered expression of PIK3R1 could modulate the activity of PI3K and result in significant metabolic outcomes. Interestingly, recent studies also found PI3K-independent functions of PIK3R1. Overall, in this article, we will provide an updated review of the metabolic functions of PIK3R1 that includes studies of PIK3R1 in various metabolic tissues using animal models, the mechanisms modulating PIK3R1 activity, and studies on the mutations of human PIK3R1 gene.

The classical dogma of glucocorticoid-induced insulin resistance is that it is caused by the transcriptional activation of hepatic gluconeogenic and insulin resistance genes by the glucocorticoid receptor (GR). Here, we find that glucocorticoids also stimulate the expression of insulin-sensitizing genes, such as Irs2. The transcriptional coregulator EHMT2 can serve as a transcriptional coactivator or a corepressor. Using male mice that have a defective EHMT2 coactivation function specifically, we show that glucocorticoid-induced Irs2 transcription is dependent on liver EHMT2's coactivation function and that IRS2 play a key role in mediating the limitation of glucocorticoid-induced insulin resistance by EHMT2's coactivation. Overall, we propose a model in which glucocorticoid-regulated insulin sensitivity is determined by the balance between glucocorticoid-modulated insulin resistance and insulin sensitizing genes, in which EHMT2 coactivation is specifically involved in the latter process.

It is well established that chronic glucocorticoid exposure causes hyperglycemia. While glucocorticoid receptor (GR) stimulates hepatic gluconeogenic gene transcription, additional mechanisms are activated by chronic glucocorticoid exposure to enhance gluconeogenesis. We found that chronic glucocorticoid treatment activated sphingosine-1-phosphate (S1P)-mediated signaling. Hepatic knockdown of hepatic S1P receptor 1 (S1PR1) had no effect on chronic glucocorticoid-induced glucose intolerance but elevated fasting plasma insulin levels. In contrast, hepatic S1PR3 knockdown exacerbated chronic glucocorticoid-induced glucose intolerance without affecting fasting plasma insulin levels. Finally, hepatic S1PR2 knockdown attenuated chronic glucocorticoid-induced glucose intolerance and reduced fasting plasma insulin levels. Here, we focused on dissecting the role of S1PR2 signaling in chronic glucocorticoid response on glucose homeostasis. We found that chronic glucocorticoid-induced hepatic gluconeogenesis, gluconeogenic gene expression, and GR recruitment to the glucocorticoid response elements (GREs) of gluconeogenic genes were all reduced in hepatic S1PR2 knockdown male mice. Hepatic S1PR2 knockdown also enhanced glucocorticoid suppression of RAR-related orphan receptor γ (RORγ) expression. Hepatic RORγ overexpression in hepatic S1PR2 knockdown mice restored glucocorticoid-induced glucose intolerance, gluconeogenic gene expression, and GR recruitment to their GREs. Conversely, RORγ antagonist and the reduction of hepatic RORγ expression attenuated such glucocorticoid effects. Thus, chronic glucocorticoid exposure induces an S1PR2-RORγ axis to cooperate with GR to enhance hepatic gluconeogenesis. Overall, this work provides novel mechanisms of and pharmaceutical targets against steroid-induced hyperglycemia.

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