Insulin resistance and Alzheimer's disease.

Department of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
BMB reports (Impact Factor: 1.99). 09/2009; 42(8):475-81. DOI: 10.5483/BMBRep.2009.42.8.475
Source: PubMed

ABSTRACT Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.

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  • Perspectives on Psychological Science 01/2014; 9(1):88-90. DOI:10.1177/1745691613514058 · 4.89 Impact Factor
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    ABSTRACT: A growing body of evidence supports the concept that type 3 diabetes (T3DM) is a neuroendocrine disease with abnormalities in brain glucose utilization and responsiveness to insulin and insulin-like growth factor (IGF) activation. In addition, deregulated glucose metabolism has a role in neurodegeneration and neuronal loss (usually accompanied by T3DM) along with multiple pathogenic factors including oxidative stress and mitochondrial dysfunction. Moreover, impaired insulin signaling can disturb both amyloid precursor protein (APP) processing and amyloid-beta (Aβ) clearance. This leads to increased neurotoxic effects of Aβ on neurons ending up with possible neurodegeneration and neuronal cell death. In the same context, the neuronal aging is characterized by decreased mitochondrial function and increased reactive oxygen species (ROS) production, which are associated with cognitive decline. Also, accelerated cognitive decline is associated with long-term complications. These complications are due to multifactorial factors including circulatory and metabolic considerations and recurrent hypoglycemia. Most of diabetic complications can be found in T3DM, but with increased severity. This review discusses the molecular, biochemical and cellular dysfunctions in both Alzheimer’s disease (AD) and diabetes mellitus (DM) along with the causation of neuronal loss and cell death, and so called neurodegenerative disease. Also it explains the mechanism of the crosstalk of the attenuated phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)/Akt pathway and the intensified activation of glycogen synthase kinase-3-beta (GSK-3 β) pathway, due to trophic factor resistance, which eventually cause abnormal hyperphosphorylated tau and impaired tau gene expression proceeding neurodegeneration. Also, it discusses the relationship between T3DM and AD based on the fact that both the processing of AβPP and the clearance of Aβ are attributed to impaired insulin signaling in the brain. Additionally, it focuses on the molecular mechanism of brain insulin resistance or “T3DM” that may involve either increased serine phosphorylation of insulin receptor substrate 1 (IRS-1) protein (i.e., IRS-1 inhibition) and/or elevated degradation of IRS protein as common pathological mechanisms. Moreover, this review emphasizes on the potential link between type 2 diabetes mellitus (T2DM) and AD that might have devastating impacts on public health or healthcare systems such as socio-economic burdens. Lastly, possible biomarkers and insulin-related therapeutic strategies are suggested to help improve the early detection, diagnosis, and treatment of T3DM or AD by slowing down their progressive nature or even halt their future complications.
    04/2015, Degree: Master, Supervisor: Dr. David Albers
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