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      Cognitive impairment in diabetic patients: Can diabetic control prevent cognitive decline?

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          Abstract

          It is well recognized that the prevalence of dementia is higher in diabetic patients than non‐diabetic subjects. The incidence of diabetes has been increasing because of dramatic changes in lifestyles, and combined with longer lifespans as a result of advances in medical technology, this has brought about an increase in the number of elderly diabetic patients. Together, aging and diabetes have contributed to dementia becoming a serious problem. Progression to dementia reduces quality of life, and imposes a burden on both patients themselves and the families supporting them. Therefore, preventing the complication of dementia will become more and more important in the future. Although many mechanisms have been considered for an association between diabetes and cognitive dysfunction, glucose metabolism abnormalities such as hyperglycemia and hypoglycemia, and insulin action abnormalities such as insulin deficiency and insulin resistance can be causes of cognitive impairment. Recent large‐scale longitudinal studies have found an association between glycemic control and cognitive decline, although it is still unclear how cognitive decline might be prevented by good glycemic control. However, at an early stage, it is necessary to detect moderate cognitive dysfunction and try to reduce the risk factors for it, which should result in prevention of dementia, as well as vascular events. In the present review, in addition to outlining an association between diabetes and cognitive function, we discuss how glycemic control and cognitive decline are related.

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          Most cited references75

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          The role of apolipoprotein E in Alzheimer's disease.

          The epsilon4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Abeta aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE epsilon4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.
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            An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

            Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
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              Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders.

              Late-onset Alzheimer's disease (AD) is a multifactorial and heterogeneous disorder with major risk factors including advanced age, presence of an apolipoprotein E epsilon4 (APOE4) allele, and family history of AD. Other risk factors may be obesity and diabetes and related disorders, which are highly prevalent. We reviewed longitudinal epidemiological studies of body mass, diabetes, metabolic syndrome, and glucose and insulin levels on risk for AD. We conducted meta-analyses of the results from these studies. For obesity assessed by body mass index, the pooled effect size for AD was 1.59 (95% confidence interval [CI] 1.02-2.5; z = 2.0; p = .042), and for diabetes, the pooled effect size for AD was 1.54 (95% CI 1.33-1.79; z = 5.7; p < .001). Egger's test did not find significant evidence for publication bias in the meta-analysis for obesity (t = -1.4, p = .21) or for diabetes (t = -.86, p = .42). Since these disorders are highly comorbid, we conducted a meta-analysis combining all studies of obesity, diabetes, and abnormal glucose or insulin levels, which yielded a highly significant pooled effect size for AD of 1.63 (95% CI 1.39-1.92; z = 5.9; p < .001). Obesity and diabetes significantly and independently increase risk for AD. Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD. Physiological changes common to obesity and diabetes plausibly promote AD. Published by Elsevier Inc.
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                Author and article information

                Journal
                J Diabetes Investig
                J Diabetes Investig
                10.1111/(ISSN)2040-1124
                JDI
                Journal of Diabetes Investigation
                Wiley-Blackwell
                2040-1116
                2040-1124
                29 August 2012
                18 October 2012
                : 3
                : 5 ( doiID: 10.1111/jdi.2012.3.issue-5 )
                : 413-423
                Affiliations
                [ 1 ] Department of Diabetes and Endocrine Internal MedicineChubu Rosai Hospital NagoyaJapan
                [ 2 ] Center for Preventive MedicineChubu Rosai Hospital NagoyaJapan
                [ 3 ] Department of NeurologyChubu Rosai Hospital NagoyaJapan
                Author notes
                [*] [* ] Corresponding author. Takahiko Kawamura Tel.: +81‐52‐652‐5511 Fax: +81‐52‐651‐5567

                E‐mail address: kawamura.hsc@ 123456chubuh.rofuku.go.jp

                Article
                JDI234
                10.1111/j.2040-1124.2012.00234.x
                4019239
                24843599
                318f8720-e400-4a60-ba4c-546fb4591693
                © 2012 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd© 2012 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd
                History
                : 03 June 2012
                : 27 June 2012
                Page count
                Pages: 11
                Categories
                Review Article
                Review Article
                Custom metadata
                2.0
                jdi234
                October 2012
                Converter:WILEY_ML3GV2_TO_NLM version:3.9.3 mode:remove_FC converted:04.02.2014

                cognitive function,diabetes mellitus,glycemic control

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