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      Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model


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          Diabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aβ) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined.


          In this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses.


          Treatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aβ deposition and the level of hyper-phosphorylated Tau protein.


          The results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer’s disease-related pathology.

          Most cited references55

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          Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

          Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.
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            Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease.

            Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.
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              High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice.

              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.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                17 August 2020
                : 14
                : 3325-3336
                [1 ]Department of Nutrition, Dietetics and Hospitality Management, Auburn University , Auburn, AL 36849, USA
                [2 ]Department of Physiology, Laboratory of Diabetes and Exercise Metabolism, College of Graduate Studies, Midwestern University , Glendale, AZ 85308, USA
                Author notes
                Correspondence: Jeganathan Ramesh Babu Department of Nutrition, Dietetics and Hospitality Management, Auburn University , Auburn, AL36849, USA Tel +1 334 844 3840 Fax +1 334 844 3268 Email jeganrb@auburn.edu
                Author information
                © 2020 Li et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 13 February 2020
                : 06 July 2020
                Page count
                Figures: 5, Tables: 2, References: 63, Pages: 12
                Original Research

                Pharmacology & Pharmaceutical medicine
                isoflavones,leptin-deficient mice,brain injury,insulin signaling,amyloid beta


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