Open Chromatin State of Dpp4 With Glucocorticoid Treatment-Setting up Shop for Metasteroid Diabetes?

Glucocorticoids are effective in posttransplant immunosuppression and provide symptomatic relief in autoimmune diseases, chronic inflammatory diseases, and allergies. They also repress the transcriptional program of proinflammatory cytokines and their secretion. Glucocorticoid treatment is often only temporary to maintain an appropriate benefit-risk ratio. Despite their clear clinical benefit, glucocorticoids can worsen preexisting diabetes and cause insulin resistance and hyperglycemia, leading to “metasteroid diabetes.” Uto et al (1) report that hyperglycemia-induced by 2 years of glucocorticoid treatment persists for 2 years after steroid discontinuation despite antidiabetic treatment, including exogenous insulin. Delineating the cause of this sustained metabolic reprogramming and memory may improve diagnostics, treatment tailoring, and provide insight into the long-term effects of glucocorticoid treatment.

Glucocorticoids reduce insulin sensitivity, promote hepatic gluconeogenesis, and reduce glucose transport in skeletal muscle. Uto et al (1) used a transient dexamethasone-loading mouse model, which revealed that the prolonged hyperglycemia and glucose intolerance were accompanied by impaired in vivo glucose-stimulated insulin secretion. Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone released into circulation upon nutrient intake that stimulates insulin secretion from the pancreas in a glucose-dependent manner. The authors observed a significant decrease in serum active GLP-1 in dexamethasone-loaded mice compared to controls (1). Additionally, the regulator of incretin bioactivity, dipeptidyl peptidase 4 (DPP4), displayed enhanced serum activity in dexamethasone-loaded mice (1). The hyperglycemic role of enhanced DPP4 in type 2 diabetes (T2D) is well defined and clinically targeted with catalytic inhibitors. Therefore, these preclinical data reveal a consistent increase in plasma DPP4 activity in metasteroid diabetes as observed in metabolic syndrome, type 1 diabetes, and T2D.

DPP4 is a glucocorticoid-responsive gene via its 2 glucocorticoid-responsive promoter elements (2). DPP4 mediates glucocorticoid-induced macrophage migration, which is prevented by DPP4 inhibitors (DPP4i) sitagliptin and linagliptin (2). Uto and colleagues (1) report significant increases in Dpp4 expression and promoter histone H3 lysine-9 acetylation (H3K9Ac) enrichment in blood mononuclear cells, suggesting an “open chromatin structure state” in the Dpp4 promoter region compared to controls, even after dexamethasone discontinuation. Whether this glucocorticoid-induced Dpp4 promoter histone hyperacetylation occurs in other tissues, such as adipose or liver, remains to be solved. Still, this epigenetic modification in mononuclear cells may be unique to metasteroid diabetes as neither DPP4 activity nor gene expression changes specifically in mononuclear cells isolated from patients with T2D compared to healthy individuals (3). Rather, enhanced release of DPP4 protein from blood mononuclear cells is observed in patients with T2D compared to samples from healthy individuals. Additionally, proinflammatory mediators such as lipopolysaccharide (LPS) upregulate plasma DPP4 activity. Sitagliptin, however, while robustly inhibiting both plasma and bone marrow DPP4 activity, does not attenuate bone marrow proinflammatory cytokine levels upon LPS stimulation and potentiates soluble DPP4 release (4). Uto et al (1) reveal a robust regulation of DPP4 activity and expression in the context of immunosuppression. Therefore, it is possible that transcriptional upregulation of Dpp4 versus shedding of DPP4 to the circulation from blood mononuclear cells may be differentially regulated in metasteroid diabetes versus T2D.

The dexamethasone-mediated prolonged reduction in active GLP-1 secretion observed by Uto and colleagues (1) was 2-fold: first, serum DPP4 activity was elevated even 36 days after treatment discontinuation, and second, messenger RNA (mRNA) expression of the intestinal processing enzyme for GLP-1, prohormone convertase 1/3 (Pc1/3) was significantly reduced during dexamethasone-loading yet returned to baseline post-treatment discontinuation (1). By contrast, in patients with T2D, intestinal PCSK1/3 mRNA expression increases while the density of PC1/3+ cells decreases compared to body mass index (BMI)-matched healthy individuals (5). At the insulinotropic site of GLP-1 action, pancreatic islets from patients with T2D reveal decreased GLP-1 receptor (GLP1R) mRNA expression, where methylation in the promoter positively correlates with BMI and glycated hemoglobin A1c (6). Assuming that this enhanced promoter methylation and reduction in islet GLP1R expression is prevalent across patients with diabetes, incretin therapies (GLP-1R agonists and DPP4i) still improve glucose control, suggesting that increasing ligand exposure can maximize the insulinotropic potential of the receptors that are present. Therefore, in contrast to the pathogenesis of T2D, it appears that glucocorticoids only induce an acute effect on GLP-1 secretion without metabolic imprinting, and instead have lasting effects on its bioactivity. Moreover, this also suggests a substrate-independent regulation of DPP4 activity in the context of steroid-induced diabetes.

The clinical utility of incretin therapies in patients treated with glucocorticoids has been evaluated. In a 28-day study, sitagliptin did not improve glucocorticoid-induced glucose intolerance in a standardized meal test in men with metabolic syndrome but without an autoimmune disease (7). In a 2-day study in 8 healthy young men who did not have a first-degree relative with T2D, intravenous infusion with the GLP-1R agonist, exenatide, prevented prednisolone-induced glucose intolerance but also lowered plasma insulin throughout the standardized meal test (8). Instead, exenatide infusion decreased glucagon secretion and gastric emptying, likely driving the improved glucose tolerance (8). So far, only short-term studies have been highlighted.

Studies controlling for patients with a family history of diabetes demonstrate that glucocorticoids do not simply catalyze a preexisting glucose metabolism disorder. These preclinical data reveal that enhanced DPP4 activity with glucocorticoid treatment is associated with changes in Dpp4 chromatin state in peripheral blood mononuclear cells rather than a response to insulin resistance (1). Considering the wide range in the percentage of patients that develop steroid-induced hyperglycemia, characterizing the incidence of enhanced circulating DPP4 activity in these patients would help determine whether elevations in DPP4 always accompany steroid use. Even more, determining if increased DPP4 activity extends beyond treatment discontinuation in these patients would highlight a biomarker for this metabolic reprogramming.

Overall, the studies performed by Uto et al (1) suggest that epigenetic changes drive the prolonged hyperglycemia with glucocorticoid use. Given the widespread use of glucocorticoids for acute and chronic conditions, understanding the prevalence of metasteroid diabetes in these patients and the interplay with already emerging long-term effects is critical.