Transient Dexamethasone Loading Induces Prolonged Hyperglycemia in Male Mice With Histone Acetylation in Dpp-4 Promoter

Abstract

Glucocorticoid causes hyperglycemia which is common in patients with or without diabetes. We experience prolonged hyperglycemia even after the discontinuation of glucocorticoid use. In the present study, we examined time course of blood glucose level in the patients of our hospital who received transient glucocorticoid treatment. In addition, the mechanism of prolonged hyperglycemia was investigated by using dexamethasone (Dexa)-treated mice and cultured cells. The blood glucose level in glucose tolerance test, level of insulin and glucagon-like peptide 1 (GLP-1) and the activity of dipeptidyl peptidase 4 (DPP-4) were examined during and after Dexa-loading in mice, with histone acetylation level of the promoter region. Mice showed prolonged hyperglycemia during and after transient Dexa-loading accompanied by persistently lower blood GLP-1 level and higher activity of DPP-4. The expression level of Dpp-4 was increased in the mononuclear cells and the promoter region of Dpp-4 was hyperacetylated during and after the transient Dexa treatment. In vitro experiments also indicated development of histone hyperacetylation in the Dpp-4 promoter region during and after Dexa treatment. The upregulation of Dpp-4 in cultured cells was significantly inhibited by a histone acetyltransferase inhibitor. Moreover, the histone hyperacetylation induced by Dexa was reversible by the treatment with a sirtuin histone deacetylase activator, nicotinamide mononucleotide. We identified persistent reduction in blood GLP-1 level with hyperglycemia during and after Dexa treatment in mice, associated with histone hyperacetylation of promoter region of Dpp-4. The results unveil a novel mechanism of glucocorticoid-induced hyperglycemia, and suggest therapeutic intervention through epigenetic modification of Dpp-4.

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

“…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.…”

“…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 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.…”

“…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.…”