Prediction of the Interactions of a Large Number of Per- and Poly-Fluoroalkyl Substances with Ten Nuclear Receptors.

Per- and poly-fluoroalkyl substances (PFASs) are persistent, toxic chemicals that pose significant hazards to human health and the environment. Screening large numbers of chemicals for their ability to act as endocrine disruptors by modulating the activity of nuclear receptors (NRs) is challenging because of the time and cost of in vitro and in vivo experiments. For this reason, we need computational approaches to screen these chemicals and quickly prioritize them for further testing. Here, we utilized molecular modeling and machine-learning predictions to identify potential interactions between 4545 PFASs with ten different NRs. The results show that some PFASs can bind strongly to several receptors. Further, PFASs that bind to different receptors can have very different structures spread throughout the chemical space. Biological validation of these in silico findings should be a high priority.

The Role of PIK3R1 in Metabolic Function and Insulin Sensitivity.

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.

Chronic Glucocorticoid Exposure Induced an S1PR2-RORγ Axis to Enhance Hepatic Gluconeogenesis in Male Mice.

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.

Transcriptional coactivation by EHMT2 restricts glucocorticoid-induced insulin resistance in a study with male mice.

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.

The vitamin D receptor as a potential target for the toxic effects of per- and polyfluoroalkyl substances (PFASs): An in-silico study.

Due to their persistence and toxicity, perfluoroalkyl and polyfluoroalkyl substances (PFASs) constitute significant hazards to human health and the environment. Their effects include immune suppression, altered hormone levels, and osteoporosis. Recently, the most studied PFAS, perfluorooctanoic acid (PFOA), was shown to competitively binding to the Vitamin D receptor (VDR). VDR plays a crucial role in regulating genes involved in maintaining immune, endocrine, and calcium homeostasis, suggesting it may be a target for at least some of the health effects of PFAS. Hence, this study examined the potential binding of 5206 PFASs to VDR using molecular docking, molecular dynamics, and free energy binding calculations. We identified 14 PFAS that are predicted to interact strongly with VDR, similar to the natural ligands. We further investigated the interactions of VDR with 256 PFASs of established commercial importance. Eighty-three (32%) of these 256 commercially important PFAS were predicted to be stronger binders to VDR than PFOA. At least 16 PFASs of regulatory importance, because they have been identified in water supplies and human blood samples, were also more potent binders to VDR than PFOA. Further, PFASs are usually found together in contaminated drinking water and human blood samples, which raises the concern that multiple PFASs may act together as a mixture on VDR function, potentially producing harmful effects on the immune, endocrine, and bone homeostasis.

The glucocorticoid receptor represses, whereas C/EBPß can enhance or repress CYP26A1 transcription.

Retinoic acid (RA) counters insulin's metabolic actions. Insulin reduces liver RA biosynthesis by exporting FoxO1 from nuclei. RA induces its catabolism, catalyzed by CYP26A1. A CYP26A1 contribution to RA homeostasis with changes in energy status had not been investigated. We found that glucagon, cortisol, and dexamethasone decrease RA-induced CYP26A1 transcription, thereby reducing RA oxidation during fasting. Interaction between the glucocorticoid receptor and the RAR/RXR coactivation complex suppresses CYP26A1 expression, increasing RA's elimination half-life. Interaction between CCAAT-enhancer-binding protein beta (C/EBPß) and the major allele of SNP rs2068888 enhances CYP26A1 expression; the minor allele restricts the C/EBPß effect on CYP26A1. The major and minor alleles associate with impaired human health or reduction in blood triglycerides, respectively. Thus, regulating CYP26A1 transcription contributes to adapting RA to coordinate energy availability with metabolism. These results enhance insight into CYP26A1 effects on RA during changes in energy status and glucocorticoid receptor modification of RAR-regulated gene expression.

2',3',4'-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism.

BACKGROUND: Menopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety concerns with long-term treatment. We investigated the ability of 2',3',4'-trihydroxychalcone (2',3',4'-THC) to modulate estrogen receptor (ER)-mediated responses in order to find drug candidates that could potentially prevent the adverse effects of long-term MHT treatment. METHODS: Transfection assays, real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2',3',4'-THC on gene regulation. Radioligand binding studies were used to determine if 2',3',4'-THC binds to ERα. Cell proliferation was examined in MCF-7 breast cancer cells by using growth curves and flow cytometry. Western blots were used to determine if 2',3',4'-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes. RESULTS: The 2',3',4'-THC/E2 combination produced a synergistic activation with ERα on reporter and endogenous genes in human U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless they were treated with 2',3',4'-THC and E2 at the same time. 2',3',4'-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced activation of MAPK and c-MYC transcription. The antiproliferative mechanism of 2',3',4'-THC differs from selective estrogen receptor modulators (SERMs) because 2',3',4'-THC did not bind to the E2 binding site in ERα like SERMs. CONCLUSION: Our study suggests that 2',3',4'-THC may represent a new class of ERα modulators that do not act as a direct agonists or antagonists. We consider 2',3',4'-THC to be a reprogramming compound, since it alters the activity of ERα on gene regulation and cell proliferation without competing with E2 for binding to ERα. The addition of a reprogramming drug to estrogens in MHT may offer a new strategy to overcome the adverse proliferative effects of estrogen in MHT by reprogramming ERα as opposed to an antagonist mechanism that involves blocking the binding of estrogen to ERα.

The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure.

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.

Chronic arsenic exposure impairs adaptive thermogenesis in male C57BL/6J mice.

The global prevalence of type 2 diabetes (T2D) has doubled since 1980. Human epidemiological studies support arsenic exposure as a risk factor for T2D, although the precise mechanism is unclear. We hypothesized that chronic arsenic ingestion alters glucose homeostasis by impairing adaptive thermogenesis, i.e., body heat production in cold environments. Arsenic is a pervasive environmental contaminant, with more than 200 million people worldwide currently exposed to arsenic-contaminated drinking water. Male C57BL/6J mice exposed to sodium arsenite in drinking water at 300 µg/L for 9 wk experienced significantly decreased metabolic heat production when acclimated to chronic cold tolerance testing, as evidenced by indirect calorimetry, despite no change in physical activity. Arsenic exposure increased total fat mass and subcutaneous inguinal white adipose tissue (iWAT) mass. RNA sequencing analysis of iWAT indicated that arsenic dysregulated mitochondrial processes, including fatty acid metabolism. Western blotting in WAT confirmed that arsenic significantly decreased TOMM20, a correlate of mitochondrial abundance; PGC1A, a master regulator of mitochondrial biogenesis; and, CPT1B, the rate-limiting step of fatty acid oxidation (FAO). Our findings show that chronic arsenic exposure impacts the mitochondrial proteins of thermogenic tissues involved in energy expenditure and substrate regulation, providing novel mechanistic evidence for arsenic's role in T2D development.

A State-of-the-Science Review of Arsenic's Effects on Glucose Homeostasis in Experimental Models.

BACKGROUND: The prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear. OBJECTIVES: We conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development. METHODS: We explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings. RESULTS: While several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic ß-cell dysfunction. DISCUSSION: This review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517.

An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice.

Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders.

Glucocorticoid Receptor and Adipocyte Biology.

Glucocorticoids are steroid hormones that play a key role in metabolic adaptations during stress, such as fasting and starvation, in order to maintain plasma glucose levels. Excess and chronic glucocorticoid exposure, however, causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. Studies in animal models of metabolic disorders frequently demonstrate that suppressing glucocorticoid signaling improves insulin sensitivity and metabolic profiles. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator. The adipocyte is one cell type that contributes to whole body metabolic homeostasis under the influence of GR. Glucocorticoids' functions on adipose tissues are complex. Depending on various physiological or pathophysiological states as well as distinct fat depots, glucocorticoids can either increase or decrease lipid storage in adipose tissues. In rodents, glucocorticoids have been shown to reduce the thermogenic activity of brown adipocytes. However, in human acute glucocorticoid exposure, glucocorticoids act to promote thermogenesis. In this article, we will review the recent studies on the mechanisms underlying the complex metabolic functions of GR in adipocytes. These include studies of the metabolic outcomes of adipocyte specific GR knockout mice and identification of novel GR primary target genes that mediate glucocorticoid action in adipocytes.

Fighting obesity by targeting factors regulating beige adipocytes.

PURPOSE OF REVIEW: The current review provides an update on secreted factors and mechanisms that promote a thermogenic program in beige adipocytes, and their potential roles as therapeutic targets to fight obesity. RECENT FINDINGS: We outline recent studies revealing unrecognized mechanisms controlling beige adipocyte physiology, and summarize in particular those that underlie beige thermogenesis independently of classical uncoupling. We also update strategies aimed at fostering beige adipogenesis and white-to beige adipocyte conversion. Finally, we summarize newly identified endogenous secreted factors that promote the thermogenic activation of beige adipocytes and discuss their therapeutic potential. SUMMARY: The identification of novel endogenous factors that promote beiging and regulate beige adipocyte-specific physiological pathways opens up new avenues for therapeutic engineering targeting obesity and related metabolic disorders.

The C-terminal fibrinogen-like domain of angiopoietin-like 4 stimulates adipose tissue lipolysis and promotes energy expenditure.

Angptl4 (Angiopoietin-like 4) is a circulating protein secreted by white and brown adipose tissues and the liver. Structurally, Angptl4 contains an N-terminal coiled-coil domain (CCD) connected to a C-terminal fibrinogen-like domain (FLD) via a cleavable linker, and both full-length Angptl4 and its individual domains circulate in the bloodstream. Angptl4 inhibits extracellular lipoprotein lipase (LPL) activity and stimulates the lipolysis of triacylglycerol stored by adipocytes in the white adipose tissue (WAT). The former activity is furnished by the CCD, but the Angptl4 domain responsible for stimulating adipocyte lipolysis is unknown. We show here that the purified FLD of Angptl4 is sufficient to stimulate lipolysis in mouse primary adipocytes and that increasing circulating FLD levels in mice through adenovirus-mediated overexpression (Ad-FLD) not only induces WAT lipolysis in vivo but also reduces diet-induced obesity without affecting LPL activity. Intriguingly, reduced adiposity in Ad-FLD mice was associated with increased oxygen consumption, fat utilization, and the expression of thermogenic genes (Ucp1 and Ppargc1a) in subcutaneous WAT. Moreover, Ad-FLD mice exhibited increased glucose tolerance. Chronically enhancing WAT lipolysis could produce ectopic steatosis because of an overflow of lipids from the WAT to peripheral tissues; however, this did not occur when Ad-FLD mice were fed a high-fat diet. Rather, these mice had reductions in both circulating triacylglycerol levels and the mRNA levels of lipogenic genes in the liver and skeletal muscle. We conclude that separating the FLD from the CCD-mediated LPL-inhibitory activity of full-length Angptl4 reveals lipolytic and thermogenic properties with therapeutic relevance to obesity and diabetes.

The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ.

Chronic glucocorticoid exposure is associated with the development of insulin resistance. We showed that glucocorticoid-induced insulin resistance was attenuated upon ablation of Angptl4, a glucocorticoid target gene encoding the secreted protein angiopoietin-like 4, which mediates glucocorticoid-induced lipolysis in white adipose tissue. Through metabolomic profiling, we revealed that glucocorticoid treatment increased hepatic ceramide concentrations by inducing enzymes in the ceramide synthetic pathway in an Angptl4-dependent manner. Angptl4 was also required for glucocorticoids to stimulate the activities of the downstream effectors of ceramide, protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ). We further showed that knockdown of PP2A or inhibition of PKCζ or ceramide synthesis prevented glucocorticoid-induced glucose intolerance in wild-type mice. Moreover, the inhibition of PKCζ or ceramide synthesis did not further improve glucose tolerance in Angptl4-/- mice, suggesting that these molecules were major downstream effectors of Angptl4. Overall, our study demonstrates the key role of Angptl4 in glucocorticoid-augmented hepatic ceramide production that induces whole-body insulin resistance.

Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis.

Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone-sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (also called p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by glucocorticoids in wild-type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice. Our data demonstrated a novel role of Pik3r1 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of glucocorticoids. Thus, the inhibition of Pik3r1 in adipocytes could alleviate lipid disorders caused by excess glucocorticoid exposure.

G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance.

The glucose-6-phosphatase catalytic subunit 2 (G6PC2) gene encodes an islet-specific glucose-6-phosphatase catalytic subunit. G6PC2 forms a substrate cycle with glucokinase that determines the glucose sensitivity of insulin secretion. Consequently, deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin. Although chronic elevation of FBG is detrimental to health, glucocorticoids induce G6PC2 expression, suggesting that G6PC2 evolved to transiently modulate FBG under conditions of glucocorticoid-related stress. We show, using competition and mutagenesis experiments, that the synthetic glucocorticoid dexamethasone (Dex) induces G6PC2 promoter activity through a mechanism involving displacement of the islet-enriched transcription factor MafA by the glucocorticoid receptor. The induction of G6PC2 promoter activity by Dex is modulated by a single nucleotide polymorphism, previously linked to altered FBG in humans, that affects FOXA2 binding. A 5-day repeated injection paradigm was used to examine the chronic effect of Dex on FBG and glucose tolerance in wild-type (WT) and G6pc2 knockout mice. Acute Dex treatment only induces G6pc2 expression in 129SvEv but not C57BL/6J mice, but this chronic treatment induced G6pc2 expression in both. In 6-hour fasted C57BL/6J WT mice, Dex treatment lowered FBG and improved glucose tolerance, with G6pc2 deletion exacerbating the decrease in FBG and enhancing the improvement in glucose tolerance. In contrast, in 24-hour fasted C57BL/6J WT mice, Dex treatment raised FBG but still improved glucose tolerance, with G6pc2 deletion limiting the increase in FBG and enhancing the improvement in glucose tolerance. These observations demonstrate that G6pc2 modulates the complex effects of Dex on both FBG and glucose tolerance.

G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress.

The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress.