Insulin and IGF-I prevent brain atrophy in diabetic rats independently of hyperglycemia
Date
2009
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Abstract
The causation of brain atrophy associated with dementia in diseases such as diabetes and Alzheimer's Disease (AD) is very poorly understood. There are 20.8 million patients in US with diabetes, 4.5 million with AD, and the incidence of both is rising. Their combined annual treatment cost (direct and indirect) for patients with dementia exceed $148 billion. Reduced insulin and insulin-like growth factor (IGF) signaling is a common biochemical feature in brains of diabetic as well as AD patients. Rodents with knockout of brain neuronal insulin receptor display no change in glucose utilization, neurodegeneration, nor impaired learning/memory. However, IGFs may substitute for insulin or be required for its activity. The literature is virtually silent concerning the role of the widespread insulin receptors in the brain. It is possible that brain atrophy is the consequence of a concomitant decline in IGF as well as insulin levels. The causation of adult brain atrophy is understudied, and identification of the factors that help maintain normal brain mass may provide hints as to the causation of neurodegenerative disorders.
Using the streptozotocin type I diabetic rat model in which both insulin and IGF levels are known to be reduced, it is possible to study the effects of one ligand independently of the other. The purpose of this study was to test the hypothesis that insulin, IGF-I, or their combination can prevent the loss of brain mass, loss of cells, and cell type-specific proteins in the context of diabetes through processes unrelated to glucoregulation. In other words, the hypothesis is that brain atrophy is the consequence primarily of the loss of two key growth factors in the brain rather than due to hyperglycemia per se.
In the first study, either insulin or a combination of insulin and IGF was infused into the brain lateral ventricles of diabetic rats for a period of 12 weeks under conditions that had no effect on hyperglycemia. Our data showed that insulin is a potent regulator of adult brain mass, preventing the loss of brain wet, water, and dry weights independently of persisting hyperglycemia and body weight loss characteristic in diabetes. Although insulin by itself had no significant effect on brain cell loss, the combination of insulin and IGF prevented this loss, as well as loss of total protein content in brain and major cytoskeletal proteins α and β tubulin. Immunoblot data showed that important neuronal and glial proteins were reduced in content in diabetes, and treatments prevented such reductions. Myelin-associated proteolipid protein (PLP) and myelin basic protein (MBP) in oligodendrocytes, and glial fibrillary acidic protein (GFAP) in astrocytes, were all reduced in diabetes. Insulin alone as well as its combination with IGF significantly or completely prevented these reductions. Neuron-specific structural proteins light and medium neurofilaments (NF-L & NF-M), β-III tubulin, the enzyme glutaminase, and synapse-localized vesicular protein syntaxin were also significantly reduced in diabetes. The combination did, but interestingly insulin alone did not prevent all of these reductions. Immunohistochemical staining of brain slices from cortex and hippocampus revealed a visible decrease of the glial markers GFAP and PLP, as well as neuronal NF-M and β-III tubulin. In agreement with the Western blot data, the combination treatment prevented all of these decreases, whereas slices from insulin-treated rats appeared intermediate in intensity between the slices from diabetic and combination-treated rats. This was in contrast to synapse-associated proteins SNAP-25 and PSD-95, where neither insulin nor its combination with IGF exerted a significant effect on their loss, indicating that these proteins are most likely not under insulin/IGF regulation.
The above study did not reveal whether the effects of the combination were entirely due to IGF-I administration. In the second virtually identical study, the diabetic rat groups were treated either with vehicle, the combination of insulin and IGF-I, or IGF-I alone. The data showed that treatment with IGF-I alone was ineffective at preventing loss of wet, water, and dry weights in diabetes, and it did not have an effect on the reduced relative abundance of GFAP, NF-L, and NF-M, while the combination treatment confirmed the results from the first study.
Taken together, these data clearly show that insulin and the combination of insulin and IGFs can prevent brain atrophy and biochemical pathology by non-glucoregulatory processes in diabetes. The combination-treated animals benefit from a synergy between insulin and IGF-I, where both peptides most likely act through their own respective receptors. The combination treatment had effects greater than insulin or IGF-I alone, and it may do so by preventing a catabolic state in brain that precedes DNA loss. These data may have relevance for clinical encephalopathy observed in physiological states of concomitantly reduced insulin and IGFs, such as diabetes and possibly also in AD.
Using the streptozotocin type I diabetic rat model in which both insulin and IGF levels are known to be reduced, it is possible to study the effects of one ligand independently of the other. The purpose of this study was to test the hypothesis that insulin, IGF-I, or their combination can prevent the loss of brain mass, loss of cells, and cell type-specific proteins in the context of diabetes through processes unrelated to glucoregulation. In other words, the hypothesis is that brain atrophy is the consequence primarily of the loss of two key growth factors in the brain rather than due to hyperglycemia per se.
In the first study, either insulin or a combination of insulin and IGF was infused into the brain lateral ventricles of diabetic rats for a period of 12 weeks under conditions that had no effect on hyperglycemia. Our data showed that insulin is a potent regulator of adult brain mass, preventing the loss of brain wet, water, and dry weights independently of persisting hyperglycemia and body weight loss characteristic in diabetes. Although insulin by itself had no significant effect on brain cell loss, the combination of insulin and IGF prevented this loss, as well as loss of total protein content in brain and major cytoskeletal proteins α and β tubulin. Immunoblot data showed that important neuronal and glial proteins were reduced in content in diabetes, and treatments prevented such reductions. Myelin-associated proteolipid protein (PLP) and myelin basic protein (MBP) in oligodendrocytes, and glial fibrillary acidic protein (GFAP) in astrocytes, were all reduced in diabetes. Insulin alone as well as its combination with IGF significantly or completely prevented these reductions. Neuron-specific structural proteins light and medium neurofilaments (NF-L & NF-M), β-III tubulin, the enzyme glutaminase, and synapse-localized vesicular protein syntaxin were also significantly reduced in diabetes. The combination did, but interestingly insulin alone did not prevent all of these reductions. Immunohistochemical staining of brain slices from cortex and hippocampus revealed a visible decrease of the glial markers GFAP and PLP, as well as neuronal NF-M and β-III tubulin. In agreement with the Western blot data, the combination treatment prevented all of these decreases, whereas slices from insulin-treated rats appeared intermediate in intensity between the slices from diabetic and combination-treated rats. This was in contrast to synapse-associated proteins SNAP-25 and PSD-95, where neither insulin nor its combination with IGF exerted a significant effect on their loss, indicating that these proteins are most likely not under insulin/IGF regulation.
The above study did not reveal whether the effects of the combination were entirely due to IGF-I administration. In the second virtually identical study, the diabetic rat groups were treated either with vehicle, the combination of insulin and IGF-I, or IGF-I alone. The data showed that treatment with IGF-I alone was ineffective at preventing loss of wet, water, and dry weights in diabetes, and it did not have an effect on the reduced relative abundance of GFAP, NF-L, and NF-M, while the combination treatment confirmed the results from the first study.
Taken together, these data clearly show that insulin and the combination of insulin and IGFs can prevent brain atrophy and biochemical pathology by non-glucoregulatory processes in diabetes. The combination-treated animals benefit from a synergy between insulin and IGF-I, where both peptides most likely act through their own respective receptors. The combination treatment had effects greater than insulin or IGF-I alone, and it may do so by preventing a catabolic state in brain that precedes DNA loss. These data may have relevance for clinical encephalopathy observed in physiological states of concomitantly reduced insulin and IGFs, such as diabetes and possibly also in AD.
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Subject
Alzheimer's disease
brain atrophy
diabetes
encephalopathy
hyperglycemia
insulin
endocrinology
pharmacology
neurobiology