Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Non‐obese Diabetic Mice

Steroid‐induced diabetes via oral delivery of glucocorticoids is the most common form of drug‐induced hyperglycemia in adults and children. Because a variety of pathological situations require a chronic glucocorticoid regimen in humans, appropriate experimental models are required to examine and understand the metabolic alterations associated with such an approach. Therefore, the purpose of this study was to investigate how chronic oral corticosterone administration impacted specific metabolic parameters in male non‐obese diabetic mice. These mice are genetically susceptible to spontaneous development of diabetes due to destruction of pancreatic islet β‐cells, which includes T‐lymphocyte infiltration into the pancreatic tissue. Therefore, these mice are a model system of a genetically at risk population in which to test both the immunosuppressive and diabetogenic properties of oral steroid delivery. The experimental design was six weeks of corticosterone delivery via drinking water (100μg/mL), followed by a four week washout phase. Control mice received 1% ethanol vehicle in the drinking water. All mice were 12 weeks of age when the study began. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin measured by insulin tolerance test (ITT) over a 2h period, which culminated with a 22% increase in area under the curve AUC in the corticosterone group when compared with the vehicle control (p < 0.05). Overt hyperglycemia (>250mg/dL) and a 12% increase in body weight (31.3g) in the corticosterone group relative to vehicle control (28g; p < 0.01) were apparent six weeks after steroid delivery. While there was no significant difference in the absolute number of islets per pancreas between the groups, mice receiving corticosterone had a 2.5‐fold increase in insulin‐positive area (p < 0.05) relative to the vehicle control group. This increase in insulin‐positive area is most likely a compensatory expansion of the islet β‐cell population in response to insulin resistance (as measured by ITT) in the periphery. The mice in the corticosterone group also displayed a 60% decrease in insulitis (islet immune cell invasion) compared with vehicle control group six weeks after oral corticosterone delivery. In addition, there were marked increases in expression of citrate synthase (7415‐fold up vs. vehicle) and glycogen synthase (6972‐fold up vs. vehicle) genes in skeletal muscle of mice in the corticosterone group relative to vehicle control. Corticosterone‐induced hyperglycemia and changes in muscle gene expression were all completely reversed by the end of the washout phase, indicating that the metabolic parameters measured were reversible. These results are similar to those reported with human subjects receiving chronic oral delivery of glucocorticoids, indicating that male NOD mice may be an excellent translational model to mimic steroid‐induced diabetes in a genetically susceptible population. Support or Funding Information NIH P20 GM103528