Significance of Diabetes in cognitive impairment
Diabetes mellitus has many adverse effects on the brain apart from the cardiovascular and peripheral nervous system effects. The increasing prevalence of diabetes mellitus due to the sedentary lifestyles and high-calorie diets of the modern world and enhanced longevity is significant in that the risks of depression, dementia and cognitive decline is heightened.
It is known that diabetes influences the hypothalamic-pituitary-adrenal axis. However, the role of this system in diabetes-impaired cognitive decline has not been fully investigated. Stranahan and his team have attempted to study the effects of diabetes on the hippocampus, which is the part of the brain associated with recent memory, perforant path synaptic plasticity, and adult neurogenesis. They also indicated that corticosterone, a glucocorticoid, mediated the effects. The research was done in insulin-deficient rats and insulin-resistant mice.
Studies that echo similar sentiments
Another study has echoed the same idea that increased glucocorticoid levels produced dysfunction in the hippocampus and is associated with spatial learning deficits in rats (Lupien, 1998). The study showed that aging people with high levels of cortisol
showed a lower volume (14% reduction) of the hippocampus and a deficit in hippocampus-dependent memory tasks when compared to people with normal cortisol. Other studies (Issa, 1990) have mentioned that the cumulative effect of the high level of glucocorticoids produces structural and functional effects on the hippocampus. They compromise hippocampal integrity and the cognitive functions dependent on the hippocampus (Issa, 1990). Glucocorticoids are secreted from the adrenal gland after stress (Karst, 2000).
It is mentioned that these hormones affect synaptic plasticity apart from modulating ionic currents, monoaminergic transmission, and cellular viability, mostly in the hippocampus, where corticosteroid receptors are enriched. The study acknowledges the role of glucocorticoid receptors in hippocampal integrity, mental performance in aging, and psychiatric disorders (Karst, 2000). Identification of the signaling pathways of glucocorticoids helps in developing intervention strategies to reduce cognitive impairment.
Summary
Human beings with both Types I and Type II diabetes mellitus showed a greater cognitive decline when compared to similar-aged non-diabetic persons. Rodents who were made diabetic (Type I) by being given streptozocin, a pancreatic beta-cell.
The toxin showed a lesser performance in spatial learning ability. A similar result was seen. in mice with leptin receptor deficiency which had resulting Type II diabetes with Hyperglycemia, obesity and increased circulating corticosterone. Mechanism of cognitive dysfunction was, however, not discovered.
Strong synapses between neurons in the dentate gyrus of the hippocampus and the addition of new neurons are essential for mediating memory and some types of learning. This inference has been made from animal models. Streptozocin-induced diabetes in rats has indicated impairment in the long-term potentiation of synaptic transmission or plasticity of synapses. Adult neurogenesis was also impaired. As both types of diabetes demonstrate impairment in plasticity, it was obviously not due to insulin changes. People with uncontrolled diabetes had high levels of cortisol due to hyperactivity of the HPA axis. Experimental diabetes had also been known to show a high level of glucocorticoids, but the HPA activation appeared to be not directly due to hyperglycemia. Glucocorticoids had been associated with cognitive impairment in psychosocial stress, aging, and Alzheimer’s but not yet with diabetes. These findings were corroborated with animal experiments. Corticosterone and stress have been found to impair neurogenesis and synaptic plasticity in animals. The impression that diabetes also impairs cognitive functions through glucocorticoids is surmised, hence this experiment.
It was found that maintaining the normal physiological corticosterone prevented learning deficits. The sham-operated mice showed impaired cognitive function. Mice that had adrenalectomy and corticosterone replacement showed a preference for a new object or reduced impairment. Insulin deficient diabetic rats had an elevated cortisol level and thereby showed a learning impairment. The diabetic rats with adrenalectomy and cortisone replacement had no impairment.
The synaptic plasticity in mice with normal physiological corticosterone was not impaired. Picrotoxin was used to decrease local inhibition and GABAergic excitation in insulin-resistant mice, which showed a reduced LTP (long-term potentiation). Sham-operated insulin-deficient rats showed lowered LTP. The streptozocin-induced diabetic rats with intact adrenals showed a lowering of LTP. Lowering the corticosterone reversed the diabetic effects on LTP. Normalizing the glucocorticoid level, the synaptic plasticity at the perforant path at the dentate gyrus was measured. The mice and the streptozocin-induced diabetic rats showed reduced LTP in the presence of picrotoxin. The impairment was prevented by adrenalectomy and corticosterone replacement in both mice and rats.
Baseline synaptic transmission was not different in mice and controls. This was lowered in rats.
The suppression of dentate gyrus cell proliferation in diabetic rodents was caused by elevated corticosterone. Sham-operated mice showed a reduction in neuron proliferation. The diabetic mice showed no difference from the non-diabetic ones.
Lowering the corticosterone level in experimental diabetes did not have any impact on the insulin and glucose levels of any of the animals. Two groups of mice were adrenalectomized, and one group was given low dose corticosterone, and the other a high dosage. The second group showed impairment. Object recognition memory was also affected similarly.
The experiments were done with controls to prove the variations possible with two groups of experimental animals, insulin-resistant mice and insulin-deficient rats, which were sham-operated, streptozocin induced diabetic ones, adrenalectomized ones, and those with corticosterone replacement.
The results showed that diabetes-induced impairments in synaptic plasticity, neurogenesis, and cognitive impairments in the dentate gyrus of the hippocampus and that these impairments are mediated through glucocorticoids or corticosterone. The hypothesis has been proved. Maintaining the normal level of corticosterone allowed the restoration of LTP at the synapses at the perforant path-dentate gyrus and normal neurogenesis. Lowering the glucocorticoid improved the normal functions. Insulin had no role in these functions.
Limitations
The question of insulin receptor signaling has not been answered in this experiment. An increased level of corticosterone is known to influence insulin receptor signaling by reducing it. The possibility of corticosterone negatively affecting the hippocampus by reducing insulin signaling has not been studied here. The effect of diabetes on learning-induced changes in hippocampal glucose metabolism has also not been studied yet. The role of the new neuron after degeneration and injury has yet to be studied.
Salient points in critique
The literature review has taken references from reliable and authentic sources, 75 % of which are very recent sources from 2005-2007. It is therefore up-to-date and based mainly on primary sources. We can expect that the latest findings and views of the subject have been reviewed and that the present study has been derived naturally. It must be noted that the argument was well placed and worded explicitly with no superfluous language or information. The hypothesis is not mentioned as such, but the idea is evident in the title of the research paper, which also gives a good idea of the variables being studied. The study has achieved what it started out for. The problems being discussed, the methods, results, and conclusions appear suitable.
The experiments were done on animal models (adult male Sprague-Dawley rats and male mice mutant for leptin receptor), which were secured from 2 laboratories. The US National Institutes of Health guidelines were followed for animal care and experimental procedures, and the experiments were approved by the US National Institute on Aging Animal Care and Use Committee. All the animals had free access to food and water. The procedures in the various sections followed instructions in the “Supplementary methods.” Statistical analysis was done with SPSS version 11.0.
Significance was set at p<0.05. Graphs were generated with Graphpad Prism 4. The behavioral data were analyzed with repeated measures ANOVA and Tukey’s post hoc test.
The limitations have been mentioned, and guidelines for future researches have been added. A positive suggestion worth mentioning is that no study has demonstrated the effect of diabetes on learning-induced changes in hippocampal glucose metabolism. Moreover, studies that have been done on animal models need to be replicated in humans.
References
Issa, A., Gauthier, S. & Meaney, M.J.; (1990), “ Hypothalamic-pituitary-adrenal activity in aged cognitively impaired and cognitively unimpaired aged rats” Journal of Neurosci. 10, 3247–3254 (1990).
Karst, H. Y.; Karten, J. G.; Reichardt, H. M.; de Kloet, E. R.; Schütz, G. and Joëls, M., “Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers”, Nature neuroscience, Vol 3, No.10, 2000, Nature America Inc.
Lupien, Sonia J.; de Leon, Mony; de Santi, Susan; Convit, Antonio; Tarshish, Chaim and Nair, N.P.V. et al, “Cortisol levels during human aging predict hippocampal atrophy and memory deficits”, Nature Neuroscience, Vol 1, No. 1, 1998, Nature America Inc.