Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer's disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer's disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer's pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non-matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes.
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