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Aging and disease    2015, Vol. 6 Issue (5) : 304-321     DOI: 10.14336/AD.2014.1104
Review Article |
Metabolic Alterations Associated to Brain Dysfunction in Diabetes
João M. N. Duarte()
Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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From epidemiological studies it is known that diabetes patients display increased risk of developing dementia. Moreover, cognitive impairment and Alzheimer’s disease (AD) are also accompanied by impaired glucose homeostasis and insulin signalling. Although there is plenty of evidence for a connection between insulin-resistant diabetes and AD, definitive linking mechanisms remain elusive. Cerebrovascular complications of diabetes, alterations in glucose homeostasis and insulin signalling, as well as recurrent hypoglycaemia are the factors that most likely affect brain function and structure. While difficult to study in patients, the mechanisms by which diabetes leads to brain dysfunction have been investigated in experimental models that display phenotypes of the disease. The present article reviews the impact of diabetes and AD on brain structure and function, and discusses recent findings from translational studies in animal models that link insulin resistance to metabolic alterations that underlie brain dysfunction. Such modifications of brain metabolism are likely to occur at early stages of neurodegeneration and impact regional neurochemical profiles and constitute non-invasive biomarkers detectable by magnetic resonance spectroscopy (MRS).

Keywords Neurodegeneration      Diabetes      Alzheimer’s disease      Insulin      Metabolism     
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present address: Kunming Biomed International, Kunming, Yunnan, 650500, China

Issue Date: 01 October 2015
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João M. N. Duarte
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João M. N. Duarte. Metabolic Alterations Associated to Brain Dysfunction in Diabetes[J]. Aging and disease, 2015, 6(5): 304-321.
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Figure 1.  Events associated to impaired insulin signalling and leading to cognitive deterioration. Insulin regulates synaptic activity and glucose metabolism. Thus impaired insulin signalling leads to synaptic dysfunction and altered glucose homeostasis that impacts energy metabolism, osmolarity and redox balance. Furthermore, Aβ clearance and tau phosphorylation are under control of insulin/IGF-1 receptors. Hence, T2D leads to increased amount of amyloid precursor protein (APP), Aβ accumulation and tau hyperphosphorylation, leading to the formation of neurofibrillary tangles. Increased oxidative stress upon redox imbalance further affects mitochondrial metabolism and favours protein aggregation. In fact, advanced glycation end-products (AGE) in oxidative stress lead to a number of protein modifications that have functional consequences on metabolic pathways for signaling and energy production. While impaired energy metabolism may directly impact synaptic efficiency due to impaired membrane repolarisation and neurotransmitter synthesis/recycling, neurofibrillary tangles resulting from protein aggregation lead to degeneration of nerve terminals. This leads to cognitive impairment and is accompanied by astrogliosis and possibly by neuroinflamation.
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