Activation of the intrinsic cell death pathway, increased apoptosis and modulation of astrocytes in the cerebellum of diabetic rats.
ABSTRACT Poorly controlled diabetes mellitus results in structural and functional changes in many brain regions. We demonstrate that in streptozotocin-induced diabetic rats cell death is increased and proliferation decreased in the cerebellum, indicating overall cell loss. Levels of both the proform and cleaved forms of caspases 3, 6 and 9 are increased, with no change in caspases 7, 8 or 12. Colocalization of glial fibrillary acidic protein (GFAP) and cleaved caspase 3 and GFAP in TUNEL-positive cells increased in diabetic rats. Changes in GFAP levels paralleled modifications in proliferating cell nuclear antigen (PCNA), increasing at 1 week of diabetes and decreasing thereafter, and proliferating GFAP-positive cells were decreased in the cerebellum of diabetic rats. These results suggest that astrocytes are dramatically affected in the cerebellum, including an increase in cell death and a decrease in proliferation, and this could play a role in the structural and functional changes in this brain area in diabetes.
Article: Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats.[show abstract] [hide abstract]
ABSTRACT: There are an estimated 36 million dementia patients worldwide. The anticipated tripling of this number by year 2050 will negatively impact the capacity to deliver quality health care. The epidemic in diabetes is particularly troubling, because diabetes is a substantial risk factor for dementia independently of cerebrovascular disease. There is an urgent need to elucidate the pathogenesis of progressive brain atrophy, the cause of dementia, to allow rational design of new therapeutic interventions. This review summarizes recent tests of the hypothesis that the concomitant loss of insulin and insulin-like growth factors (IGFs) is the dominant cause for age-dependent, progressive brain atrophy with degeneration and cognitive decline. These tests are the first to show that insulin and IGFs regulate adult brain mass by maintaining brain protein content. Insulin and IGF levels are reduced in diabetes, and replacement of both ligands can prevent loss of total brain protein, widespread cell degeneration, and demyelination. IGF alone prevents retinal degeneration in diabetic rats. It supports synapses and is required for learning and memory. Replacement doses in diabetic rats can cross the blood-brain barrier to prevent hippocampus-dependent memory impairment. Insulin and IGFs are protective despite unabated hyperglycemia in diabetic rats, severely restricting hyperglycemia and its consequences as dominant pathogenic causes of brain atrophy and impaired cognition. These findings have important implications for late-onset alzheimer's disease (LOAD) where diabetes is a major risk factor, and concomitant decline in insulin and IGF activity suggest a similar pathogenesis for brain atrophy and dementia.Indian journal of endocrinology and metabolism. 12/2012; 16(Suppl 3):S601-10.
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ABSTRACT: The aim of this study was to identify factors that regulate the bulk of adult brain mass, and test the hypothesis that concomitantly reduced insulin and insulin-like growth factor (IGF) levels are pathogenic for brain atrophy associated with impaired learning and memory in diabetes. Doses of insulin, or insulin plus IGF-I that were too small to prevent hyperglycemia were infused for 12 weeks into the brain lateral ventricles of streptozotocin-diabetic adult rats. Brain wet, water and dry weights were significantly decreased in diabetic rats; insulin prevented these decreases. The decrease in brain DNA and protein contents in diabetic rats was prevented by the combination treatment, but not by insulin alone. Levels of several glia- and neuron-associated proteins were reduced in diabetes; these reductions were also prevented by the combination treatment. Although hyperglycemia was not prevented in plasma or cerebrospinal fluid, insulin prevented brain atrophy but not bulk DNA loss in diabetes, whereas the combination prevented both. Insulin actively prevented the loss of brain water content as well. Brain atrophy is associated with concomitantly reduced levels of insulin and IGF in other disorders such as Alzheimer's disease.Brain research 09/2009; 1303:179-94. · 2.46 Impact Factor