Type 1 diabetes, glucocorticoids and the brain: a sweet connection

Peripheral and autonomous neuropathies are well-known and devastating complications of type 1 diabetes (T1D). However, T1D can also impact the integrity of the central nervous system (CNS), and the reason why T1D affects CNS integrity remains to be elucidated. Studies on diabetic patients demonstrated mild to moderate slowing of mental speed and diminished mental flexibility. Although the alterations in cognitive functions under normal conditions are not severe, mild cognitive defects can influence everyday activities in more demanding situations. Indeed, in 2004 Sandeep et al reported that hypercortisolism in diabetic patients may contribute to their hippocampal dysfunction. To investigate disease initiation, progression, and treatments without exposing humans to unnecessary and potentially unethical risks, animal models have been developed. The physiology of mice, rats, and other animals is remarkably conserved in comparison to the human condition, and over the last 40 years several animal models have become available. We have used two animal models, i.e. a pharmacological model, the streptozotocin (STZ) treated mouse, and a genetic model the NOD mouse, which spontaneously develops type 1 diabetes. As type 1 diabetic patients, these animal models show high circulating glucocorticoid levels, increased sensitivity to stress, and morphological alteration in various brain areas. In the present study these models were used to test the hypothesis that the onset of diabetes induces first dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and subsequently hypersecretion of glucocorticoids which then renders the brain more vulnerable to metabolic insults causing damage and concomitant cognitive disturbances. The NOD model revealed a surge in ACTH release, which likely preceded the onset and progression of diabetes marked by adrenal hyperreponsiveness and hypersecretion of corticosterone. To our surprise we found in the STZ model that not the initial ACTH surge was the most proximal cause of hypercorticism in diabetes, but rather the induction of adrenocortical ACTH receptors per se. At no time-point after STZ administration ACTH levels did rise reinforcing the notion that hyperresponsiveness of the adrenals to ACTH may occur independent of the mitogenic activity of the peptide. In the same model, excess glucocorticoids rather than glycemia and insulin appeared causal to cerebral damage and mild cognitive impairment. These deficits in hippocampal function induced by high glucocorticoid concentrations were readily ameliorated by a brief treatment with the glucocorticoid receptor antagonist mifepristone. These findings make the GRs a suitable target for new therapeutic strategies aimed to normalize the disturbed hippocampal functions characteristic for diabetes neuropathology.J.E. Jurriaanse Stichting, LACDR, NWO-WOTRO, Diabetes Fonds, DFG-NWO International Research and Training Group (IRTG) Leiden-Trier, Corcept Therapeutics Inc.UBL - phd migration 201

Short-Term Environmental Enrichment Enhances Adult Neurogenesis, Vascular Network and Dendritic Complexity in the Hippocampus of Type 1 Diabetic Mice

Background: Several brain disturbances have been described in association to type 1 diabetes in humans. In animal models, hippocampal pathological changes were reported together with cognitive deficits. The exposure to a variety of environmental stimuli during a certain period of time is able to prevent brain alterations and to improve learning and memory in conditions like stress, aging and neurodegenerative processes. Methodology/Principal Findings: We explored the modulation of hippocampal alterations in streptozotocin-induced type 1 diabetic mice by environmental enrichment. In diabetic mice housed in standard conditions we found a reduction of adult neurogenesis in the dentate gyrus, decreased dendritic complexity in CA1 neurons and a smaller vascular fractional area in the dentate gyrus, compared with control animals in the same housing condition. A short exposure-10 days- to an enriched environment was able to enhance proliferation, survival and dendritic arborization of newborn neurons, to recover dendritic tree length and spine density of pyramidal CA1 neurons and to increase the vascular network of the dentate gyrus in diabetic animals. Conclusions/Significance: The environmental complexity seems to constitute a strong stimulator competent to rescue th

Regulation of structural plasticity and neurogenesis during stress and diabetes; protective effects of glucocorticoid receptor antagonists

In this chapter, we will review changes in structural plasticity of the adult hippocampus during stress and exposure to glucocorticoids (GCs). We further discuss the protective and normalizing role of glucocorticoid receptor (GR) antagonist treatment under these conditions and its implications for disorders such as depression and diabetes mellitus

Glucocorticoid receptor blockade normalizes hippocampal alterations and cognitive impairment in streptozotocin-induced type 1 diabetes mice

Type 1 diabetes is a common metabolic disorder accompanied by an increased secretion of glucocorticoids and cognitive deficits. Chronic excess of glucocorticoids per se can evoke similar neuropathological signals linked to its major target in the brain, the hippocampus. This deleterious action exerted by excess adrenal stress hormone is mediated by glucocorticoid receptors (GRs). The aim of the present study was to assess whether excessive stimulation of GR is causal to compromised neuronal viability and cognitive performance associated with the hippocampal function of the diabetic mice. For this purpose, mice had type 1 diabetes induced by streptozotocin (STZ) administration (170 mg/kg, i.p.). After 11 days, these STZ-diabetic mice showed increased glucocorticoid secretion and hippocampal alterations characterized by: (1) increased glial fibrillary acidic protein-positive astrocytes as a marker reacting to neurodegeneration, (2) increased c-Jun expression marking neuronal activation, (3) reduced Ki-67 immunostaining indicating decreased cell proliferation. At the same time, mild cognitive deficits became obvious in the novel object-placement recognition task. After 6 days of diabetes the GR antagonist mifepristone (RU486) was administered twice daily for 4 days (200 mg/kg, p.o.). Blockade of GR during early type 1 diabetes attenuated the morphological signs of hippocampal aberrations and rescued the diabetic mice from the cognitive deficits. We conclude that hippocampal disruption and cognitive impairment at the early stage of diabetes are caused by excessive GR activation due to hypercorticism. These signs of neurodegeneration can be prevented and/or reversed by GR blockade with mifepristone. © 2009 Nature Publishing Group All rights reserved.Fil: Revsin, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rekers, Niels V.. Leiden University Medical Center; Países BajosFil: Louwe, Mieke C.. Leiden University Medical Center; Países BajosFil: Saravia, Flavia Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ron De Kloet, E. Leiden University Medical Center; Países BajosFil: Oitzl, Melly S.. Leiden University Medical Center; Países Bajo