Diabetes and Insulin Injection Modalities: Effects on Hepatic and Hippocampal Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Juvenile Diabetic Male Rats

Abstract

BackgroundDysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is often encountered in diabetes, leading to several clinical complications. Our recent results showing an elevated tetrahydrocortisol/tetrahydrocorticosterone ratio in morning urine of diabetic children compared to that of controls suggest an increased nocturnal activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the former.QuestionWe hypothesized that these observations could be explained by a reduced inhibition of hepatic 11β-HSD1 activity by exogenous insulin owing to its subcutaneous (SC) administration and absence of first hepatic passage. Additionally, we hypothesized that hippocampal 11β-HSD1 activity might also be impaired by diabetes.MethodsWe therefore measured HPA axis activity and 11β-HSD1 expression and activity in liver and hippocampus in streptozotocin-induced diabetic juvenile rats treated with SC or intraperitoneal (IP) insulin.ResultsPlasma corticosterone levels were elevated in untreated diabetic rats during the resting phase and restored by both types of insulin treatment. The mRNA expression and activity of 11β-HSD1 were increased in the untreated diabetic group in liver. Although diabetes was controlled equally whatever the route of insulin administration, liver 11β-HSD1 gene expression and activity was decreased only in the IP group, suggesting that a first hepatic pass is needed for 11β-HSD1 hepatic inhibition. In hippocampus, 11β-HSD1 activity was elevated in the untreated diabetic group but restored by both types of insulin treatment. Thus, these data extend our findings in diabetic children by showing impairment of hippocampal 11β-HSD1 in diabetes and by demonstrating that IP is preferable to SC insulin administration to restore 11β-HSD1 activity in liver.

Diabetes and associated cognitive disorders: Role of the Hypothalamic Pituitary Adrenal axis

“…Given our data in T1D children [137], we hypothesized that 11β-HSD1 may also be overactivated in brain of T1D and be responsible for cognitive impairments as it is the case in old individuals. We demonstrated that 11β-HSD1 levels were increased in T1D juvenile rats hippocampus [50,51]. These studies point to a pivotal role for 11β-HSD1 in glucocorticoid excess induced by T1D and consequently of altered hippocampal function (performance on the Y-maze and recognition of a displaced object [51]).…”

“…In response to a restraint stress, the peak of secretion of corticosterone was similar between experimental groups, contrary to the recovery that was delayed in untreated diabetic rats [51], suggesting an impaired feedback mechanism as described in humans. Although insulin treatment prevented the increased levels of corticosterone in basal conditions, there was no beneficial effect under stress conditions [50]. Within hippocampus, corticosterone concentration was also increased at the nadir in untreated diabetic rats, as well as 11β-HSD1 activity.…”

Altered Cortisol Metabolism Increases Nocturnal Cortisol Bioavailability in Prepubertal Children With Type 1 Diabetes Mellitus

“…was rejected because 11β-HSD1 activity increased in healthy adults submitted to a hyperinsulinaemic euglycaemic clamp ( 20 ). However, in a rodent model of insulin-deficient diabetes, we showed that intraperitoneal insulin led to a decrease in 11β-HSD1 activity in the liver, whereas subcutaneous insulin did not ( 11 ). At the cellular level, results are contradictory regarding whether glucose control (via insulin administration) has a direct ( 21 ) or indirect inhibitory effect ( 22 ) on 11β-HSD1 transcription or activity.…”

“…In animal studies, we showed that glucocorticoid levels and 11β-HSD1 activity were elevated in diabetic rats not treated with insulin. Subcutaneous administration of insulin partially prevented glucocorticoid dysregulation by decreasing 11β-HSD1 activity in the liver ( 11 ). We also showed that insulin treatment partially rescued several hippocampus-dependent behavioural and structural changes in early onset insulin-deficient diabetic rats, as well as 11β-HSD1 activity in the hippocampus ( 12 ) indicating that the elevated bioavailability of glucocorticoids may be involved in the diabetes cognitive dysfunctions.…”