HPA axis regulation in type 1 diabetes

REVSIN, Y; DALM, S.; SARAVIA, F.; OITZL, MS; DE NICOLA, AF; DE KLOET, ER

Copenhague, Dinamarca

Congreso; EASD meeting; 2006

Background and Aims: Diabetes mellitus is associated with various cerebral disturbances in both humans and animals. Using the pharmacological model of type 1 diabetes, streptozotocin (STZ)-treated mice, we previously described that hippocampal astrocytes and neurons are strongly activated one month after diabetes induction, exhibiting also higher oxidative stress markers. Based on these results and the involvement of the hippocampus in stress-system regulation via the Hypothalamus-Pituitary-Adrenal (HPA) axis, we now examine central and peripheral markers of HPA axis activity in diabetic mice. Materials and Methods: Three months old male C57BL/6J mice were injected with STZ (170 mg/kg i.p.) or vehicle. Every other day blood samples were taken via tail incision to determine corticosterone, ACTH and glycemia levels. At the same time, body weight and food and water intake were measured. After 14 days, mice were decapitated, brain sections were processed for in situ hybrization. Results: While plasma corticosterone was elevated from day 1 to day 14 after the onset of the disease, ACTH was significantly decreased after 14 days of diabetes (diabetic=70.94 ± 8.03 ng/ml; n=6, control=158.4 ± 20.31 ng/ml; n=7, p<0.01). MR mRNA expression in the dentate gyrus of the hippocampus was significantly decreased in diabetic mice (diabetic=58.88 ± 3.32, control=69.69 ± 3.57; n=8, p<0.05). GR mRNA expression in the hippocampus and the paraventricular nucleus of the hypothalamus as well as CRH mRNA in the latter region were similar in both groups. Conclusion: The augmented corticosterone secretion occurs one day after the onset of diabetes in a condition of increased glycemia, indicating that the rise in blood glucose levels (or its consequences) are responsible for the increased corticosterone. Decreased MR mRNA in relation to decreased ACTH release in the face of exaggerated corticosterone secretion suggest a profound disturbance in HPA axis regulation, most likely including sensitization of the adrenals to ACTH. If these changes in HPA axis regulation contribute to cognitive dysfunction and an impaired ability to respond to stress will be the topic of future studies.