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

Low Dose Radiation Overcomes Diabetes-induced Suppression of Hippocampal Neuronal Cell Proliferation in Rats

We investigated the effect of low dose radiation on diabetes induced suppression of neurogenesis in the hippocampal dentate gyrus of rat. After 0.01 Gy, 0.1 Gy, 1 Gy and 10 Gy radiation was delivered, the dentate gyrus of hippocampus of streptozotocin (STZ)-induced diabetic rats were evaluated using immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU), caspase-3, and terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) staining. The number of BrdU positive cells in the non-diabetic rats, diabetic rats without radiation, diabetic rats with 0.01 Gy radiation, diabetic rats with 0.1 Gy radiation, diabetic rats with 1 Gy radiation and diabetic rats with 10 Gy radiation were 55.4±8.5/mm2, 33.3±6.4/mm2, 67.7±10.5/mm2, 66.6±10.0/mm2, 23.5±6.3/mm2and 14.3±7.2/mm2, respectively. The number of caspase-3 positive cells was 132.6±37.4/mm2, 378.6±99.1/mm2, 15.0±2.8/mm2, 57.1±16.9/mm2, 191.8±44.8/mm2and 450.4±58.3/mm2, respectively. The number of TUNEL-positive cells was 24.5±2.0/mm2, 21.7±4.0/mm2, 20.4±2.0/mm2, 18.96±2.1/mm2, 58.3±7.9/mm2, and 106.0±9.8/mm2, respectively. These results suggest low doses of radiation paradoxically improved diabetes induced neuronal cell suppression in the hippocampal dentate gyrus of rat

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

Age-related loss of brain volume and T2 relaxation time in youth with Type 1 diabetes

OBJECTIVE: Childhood-onset type 1 diabetes is associated with neurocognitive deficits, but there is limited evidence to date regarding associated neuroanatomical brain changes and their relationship to illness variables such as age at disease onset. This report examines age-related changes in volume and T2 relaxation time (a fundamental parameter of magnetic resonance imaging that reflects tissue health) across the whole brain. RESEARCH DESIGN AND METHODS: Type 1 diabetes, N = 79 (mean age 20.32 ± 4.24 years), and healthy control participants, N = 50 (mean age 20.53 ± 3.60 years). There were no substantial group differences on socioeconomic status, sex ratio, or intelligence quotient. RESULTS: Regression analyses revealed a negative correlation between age and brain changes, with decreasing gray matter volume and T2 relaxation time with age in multiple brain regions in the type 1 diabetes group. In comparison, the age-related decline in the control group was small. Examination of the interaction of group and age confirmed a group difference (type 1 diabetes vs. control) in the relationship between age and brain volume/T2 relaxation time. CONCLUSIONS: We demonstrated an interaction between age and group in predicting brain volumes and T2 relaxation time such that there was a decline in these outcomes in type 1 diabetic participants that was much less evident in control subjects. Findings suggest the neurodevelopmental pathways of youth with type 1 diabetes have diverged from those of their healthy peers by late adolescence and early adulthood but the explanation for this phenomenon remains to be clarified