Insulin resistance and Alzheimer’s disease. BMB Rep

Department of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
BMB reports (Impact Factor: 2.6). 09/2009; 42(8):475-81. DOI: 10.5483/BMBRep.2009.42.8.475
Source: PubMed


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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    • "Indeed, insulin and IGF share a high degree of structural and functional homology and each of them bind to–and activate–the receptor of the other molecule [41,42]. An increased insulin resistance of the brain has been implied to play a role in AD [5,21]. Thus, Talbot et al. demonstrated elegantly that patients with AD show a markedly reduced response to insulin in the hippocampus and the cerebellar cortex, accompanied by a greatly reduced response to IGF-I as well. "
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    ABSTRACT: The Insulin-like Growth Factor (IGF)-related system is implicated in neuroregeneration and cell repair, as well as regulating lifespan. IGF-II, one component of this system, has also been found to affect memory functions in a rat model. In this study we explored changes in the IGF-related system in patients with Alzheimer's disease (AD), including changes in IGF-II levels. We measured blood plasma and cerebrospinal fluid (CSF) levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in 72 healthy controls and 92 patients with AD. We found significantly lower blood plasma levels of IGF-II and IGFBP-3 in patients with AD, compared with controls. The levels of IGF-II and IGFBP-2 were significantly elevated in the CSF from patients with AD. We also found correlations between established CSF biomarkers for AD (tau and P-tau) and components of the IGF system. CSF and blood plasma levels of IGF-II and some of its binding proteins are changed in patients with AD. Further investigation into this area may unravel important clues to the nature of this disease.
    BMC Neurology 04/2014; 14(1):64. DOI:10.1186/1471-2377-14-64 · 2.04 Impact Factor
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    • "The nature of these associations is complex. In Alzheimer's disease (AD), research has described on the one hand that people with clinical AD, apolipoprotein E ε4 genotype and/or amyloid-β biomarkers exhibit abnormal insulin levels and insulin metabolism, while on the other hand, a history of type 2 diabetes and even normoglycemic insulin resistance increases risk for subsequent AD (Baker et al., 2010; Biessels et al., 2006; Correia et al., 2011; de la Monte, 2009; Haan, 2006; Neumann et al., 2008; Profenno et al., 2010; Schrijvers et al.; Zhao and Townsend, 2009). We recently reported direct evidence of brain insulin resistance in humans with mild cognitive impairment and AD as well as extensive abnormalities in the activation status of numerous constituents of the insulin–insulin receptor substrate-1 (IRS-1)–PI3k–Akt– mTOR and GSK3 pathways (Talbot et al., 2012). "
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    ABSTRACT: Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17days or a moderate high fat diet (HFD, 45% kcal by fat) for 8weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS(616)), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.
    Neurobiology of Disease 03/2014; 67. DOI:10.1016/j.nbd.2014.03.011 · 5.08 Impact Factor
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    • "AD has even been described as " type 3 diabetes " and it has been suggested that it could be considered mainly as a metabolic disease characterized by a progressive loss of the brain capacity to respond to insulin and insulin-like growth factor stimulation that results in cognitive impairment [11]. Peripheral insulin resistance contributes to the development of brain insulin resistance by inducing the production of toxic lipids that are able to promote neurodegeneration [11]. Thus, it has been suggested that the soaring incidence of diseases characterized by peripheral insulin resistance, such as obesity, T2DM and metabolic syndrome, might represent an important factor contributing to the current AD epidemic. "
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    ABSTRACT: Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IRβ phosphorylation and 2-deoxyglucose cellular uptake.
    European Journal of Medicinal Chemistry 11/2013; 71C:112-127. DOI:10.1016/j.ejmech.2013.11.001 · 3.45 Impact Factor
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