Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice

Abstract

Steroid-induced diabetes is the most common form of drug-induced hyperglycemia. Therefore, metabolic and immunological alterations associated with chronic oral corticosterone were investigated using male nonobese diabetic mice. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin action measured by insulin tolerance test. Body composition measurements revealed increased fat mass and decreased lean mass. Overt hyperglycemia (>250 mg/dL) manifested 6 weeks after the start of glucocorticoid administration, whereas 100% of the mice receiving the vehicle control remained normoglycemic. This phenotype was fully reversed during the washout phase and readily reproducible across institutions. Relative to the vehicle control group, mice receiving corticosterone had a significant enhancement in pancreatic insulin-positive area, but a marked decrease in CD3 cell infiltration. In addition, there were striking increases in both citrate synthase gene expression and enzymatic activity in skeletal muscle of mice in the corticosterone group relative to vehicle control. Moreover, glycogen synthase expression was greatly enhanced, consistent with elevations in muscle glycogen storage in mice receiving corticosterone. Corticosterone-induced hyperglycemia, insulin resistance, and changes in muscle gene expression were all reversed by the end of the washout phase, indicating that the metabolic alterations were not permanent. Thus, male nonobese diabetic mice allow for translational studies on the metabolic and immunological consequences of glucocorticoid-associated interventions in a mouse model with genetic susceptibility to autoimmune disease.

Glucocorticoid-Induced Metabolic Disturbances are Exacerbated in Obesity

“…Excess adiposity, such is seen in obesity, has been associated with increased insulin resistance. Previous work from our lab shows increased fat mass following 12 weeks of dexamethasone treatment (Hochberg et al 2015) in lean mice, in accordance with what others have reported (Burke et al 2017), as well as reduced insulin sensitivity. However, to our surprise, the glucocorticoid treatment in obese mice led to a lipodystrophic phenotype, which indicates the disturbances in glucose homeostasis are not a result of increased fat mass.…”

“…There is some debate as to which genes glucocorticoids are acting on to promote lipolysis. Downregulation of Pde3b (Xu et al 2009) and upregulation of β-adrenergic receptors (Lacasa et al 1988) and ATGL transcripts (Campbell et al 2011;Serr et al 2011;Shen et al 2017) have been proposed as possible mechanisms. We found ATGL, the rate limiting enzyme for adipose triglyceride lipolysis, to be synergistically activated by obesity and glucocorticoid-treatment.…”

db/dbMice Exhibit Features of Human Type 2 Diabetes That Are Not Present in Weight-Matched C57BL/6J Mice Fed a Western Diet

“…Mice were fasted for 2 h and were injected intraperitoneally with 0.75 units/kg Humulin R insulin as previously described [ 19 ]. Islet histology procedures have been described [ 19 , 20 ].…”

“…Mice were fasted for 2 h and were injected intraperitoneally with 0.75 units/kg Humulin R insulin as previously described [ 19 ]. Islet histology procedures have been described [ 19 , 20 ]. Briefly, the antibodies used were as follows: insulin (Invitrogen; 18-0067; used at 1 : 800), glucagon (Cell Signaling Technologies; 8233; used at 1 : 400), Aldh1a3 (Novus Biologicals; NBP2-15339; used at 1 : 100), and Nkx6.1 (F55A12; 1 : 200; [ 21 ]).…”

Correlation among body composition and metabolic regulation in a male mouse model of Cushing’s syndrome

“…For creating a male mouse model of Cushing's syndrome, when those mice became eight-week-old, drinking water was replaced with a 1% ethanol solution containing 100 μg/mL corticosterone (Wako Pure Chemical Industries) or a vehicle, and those mice were remained to be fed and watered ad libitum as previously reported [10][11][12]. After 4-wk corticosterone treatment, mice were anesthetized with intraperitoneal injection of sodium pentobarbital (Kyoritsu Seiyaku) at 75 mg/kg body weight and sacrificed.…”