Amyloid-β Induces Hepatic Insulin Resistance by Activating JAK2/STAT3/SOCS-1 Signaling Pathway

Zhang, Yi; Zhou, Ben; Zhang, Fang; Wu, Jingxia; Hu, Yanan; Liu, Yang; Zhai, Qiwei

doi:10.2337/db11-0499

Cited by 91 publications

(97 citation statements)

References 53 publications

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“…Third, Ab accumulates in the pancreas. 34 Zhang et al 35 found that APP/presenilin 1 (PS1) transgenic AD mice with elevated plasma Ab 40/42 levels have impaired hepatic insulin signalling and glucose/insulin tolerance and activation of the JAK2/STAT3/SOCS1 pathway. The JAK/STAT/SOCS pathway was recognized as downstream of inflammatory cytokines, by which inflammation elevates insulin resistance in the peripheral system.…”

Section: Discussionmentioning

confidence: 99%

Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

Ahmed

Elgharabawy

Al-Najjar

2017

Exp Biol Med (Maywood)

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Several aspects associated with T2D that contribute to AD and vice versa were investigated in this study. Additionally, this work reveals the role of Ab40, Ab42, insulin, HbA1c, lipid profile disturbance, CRP, D-dimer, and magnesium in the bidirectional association between T2D and the pathogenesis of AD, that is powered by their correlations, and therefore the possibility of utilizing Ab as a biochemical marker of T2D in Alzheimer's patients is recommended. Furthermore, the ameloriating effect of anti-Alzheimer's drugs on diabetes mellitus confirms this association. Hereafter, a new approach for treating insulin resistance and diabetes may be developed by new therapeutic potentials such as neutralization of Ab by anti-Ab antibodies. AbstractMild to severe forms of nervous system damage were exhibited by approximately 60-70% of diabetics. It is important to understand the association between type 2 diabetes mellitus and Alzheimer's disease. The aim of the present work is to understand the bidirectional association between type 2 diabetes and Alzheimer's disease pathogenesis, that was monitored by glycaemic status, lipid profile, amyloid beta 40 and 42 (Ab40 and Ab42), C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer and magnesium measurements, to assess the association between theses biochemical markers and each other, to estimate the possibility of utilizing the amyloid beta as biochemical marker of T2D in Alzheimer's patients, and to evaluate the effect of piracetam and memantine drugs on diabetes mellitus. This study involved 120 subjects divided into 20 healthy control (group I), 20 diabetic patients (group II), 20 Alzheimer's patients (group III), 20 diabetic Alzheimer's patients with symptomatic treatment (group IV), 20 diabetic Alzheimer's patients treated with memantine (group V), and 20 diabetic Alzheimer's patients treated with piracetam (group VI). The demographic characteristics, diabetic index, and lipid profile were monitored. Plasma amyloid beta 40 and amyloid beta 42, C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer, and magnesium were assayed. The levels of amyloid beta 40 and amyloid beta 42 were significantly elevated in diabetic Alzheimer's patients with symptomatic treatment (group IV) compared to group II (by 50.5 and 7.5 fold, respectively) and group III (by 25.4 and 2.8 fold, respectively). In groups II, III, IV, V and VI, significant and positive associations were monitored between insulin and amyloid beta 40, amyloid beta 42, C-reactive protein, total creatine kinase, and D-dimer. Diabetic markers were significantly decreased in diabetic Alzheimer's patients treated with anti-Alzheimer's drugs (especially piracetam) compared to group IV. This study reveals the role of amyloid beta 40, amyloid beta 42, insulin, HbA1c, lipid profile disturbance, C-reactive protein, D-dimer, and magnesium in the bidirectional correlation between T2D and pathogenesis of Alzheimer's disease, that is powered by their correlations, and therefore the ...

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Section: Discussionmentioning

confidence: 99%

Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

Ahmed

Elgharabawy

Al-Najjar

2017

Exp Biol Med (Maywood)

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“…In addition to the classical cytokine activators of SOCS proteins listed above, a recent study has suggested that a key regulator of SOCS1 expression in the liver might be amyloid-β, a molecule that is proposed to be responsible for the link between Alzheimer's disease and the development of liver insulin resistance [52]. Using a transgenic mouse model expressing increased levels of amyloid-β, Zhang et al [52] showed reduced insulin signalling specifically in the liver, which was associated with increased protein expression of SOCS1.…”

Section: Introductionmentioning

confidence: 97%

“…Using a transgenic mouse model expressing increased levels of amyloid-β, Zhang et al [52] showed reduced insulin signalling specifically in the liver, which was associated with increased protein expression of SOCS1. In isolated hepatocytes amyloid-β was able to increase activation of JAK2/STAT3, which resulted in elevated SOCS1 expression.…”

Section: Introductionmentioning

confidence: 98%

Suppressor of cytokine signalling (SOCS) proteins as guardians of inflammatory responses critical for regulating insulin sensitivity

Galić

Sachithanandan

Kay

et al. 2014

Biochemical Journal

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Overactivation of immune pathways in obesity is an important cause of insulin resistance and thus new approaches aimed to limit inflammation or its consequences may be effective for treating Type 2 diabetes. The SOCS (suppressors of cytokine signalling) are a family of proteins that play an essential role in mediating inflammatory responses in both immune cells and metabolic organs such as the liver, adipose tissue and skeletal muscle. In the present review we discuss the role of SOCS1 and SOCS3 in controlling immune cells such as macrophages and T-cells and the impact this can have on systemic inflammation and insulin resistance. We also dissect the mechanisms by which SOCS (1-7) regulate insulin signalling in different tissues including their impact on the insulin receptor and insulin receptor substrates. Lastly, we discuss the important findings from SOCS whole-body and tissue-specific null mice, which implicate an important role for these proteins in controlling insulin action and glucose homoeostasis in obesity.

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“…Furthermore the injection of anti Abeta-neutralizing antibodies in APPswe/PSEN1dE9 AD model mice causes decreased fasting blood glucose level and improved insulin sensitivity [31]. By examining postmortem brain tissues of AD patients at different stages, it was found that AD might be a neuroendocrine disease associated with insulin signaling.…”

mentioning

confidence: 99%

“…Some studies have suggested that the main link between T2DM and AD is the disorder in insulin signaling and it was found that plasma Abeta and Abeta 1-42 levels are increased in patients with hyperglycemia [31][32][33] and also, Abeta impairs insulin signaling in mouse liver and cultured hepatocytes by activating JAK2/STAT3/ SOCS-1 signaling pathway [31]. Furthermore the injection of anti Abeta-neutralizing antibodies in APPswe/PSEN1dE9 AD model mice causes decreased fasting blood glucose level and improved insulin sensitivity [31].…”

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confidence: 99%

Insulin Resistance: A Bridge between T2DM and Alzheimer’s Disease

Giacomazza¹,

Carlo²

2013

J Diabetes Metab

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Type 2 diabetes mellitus (T2DM) is a metabolic disorder in which insulin is no longer able to control the levels of blood sugar.A westernstyle diet in combination with the lack of exercise is the mainfactor for the increase of T2DM. While in the past people onlydeveloped T2DM at older age ("old age diabetes"), now even teenagerscontract T2DMbecause of the change in the lifestyle. Western diet is characterized by the exponential increase in the consumption of highly treated foods without appropriate nutrients for systemic metabolic functions or with added ingredients that prejudice protective actions of natural food constituent.T2DM is caused by insulin resistance in the tissues, no longer able to respond to the hormone action. It is most frequently associated with aging, a family history of diabetes, obesity, and failure of exercise.The insulin, ahormone produced by the beta-cells of the pancreas, is the key biomolecule for the regulation of carbohydrate and lipid metabolism. Although its action in body organs mainly concerns the glucose homeostasis, in Central Nervous System insulin performs several functions such as regulation of glucose metabolism, food intake and body weight, fertility and reproduction [1] and others not yet completely known. In particular, the high density of insulin receptors in the hippocampus and cerebral cortex regions has suggested its participation in learning and memory process. The administration of insulin to both humans and animal models has induced an enhancement of the memory function [2] and the treatment with insulin has given in several animal models beneficial effects to prevent memory loss after ischemia episodes whereas no effects are observed with glucose alone [3]. Insulin is also involved in the synaptic plasticity, for example, it as been show that insulin allows the long-lasting enhancement of GABA receptormediated synaptic transmission [4] and promote the internalization of AMPA receptors from the neuron synaptic membrane causing a long-term depression (LTD) of excitatory synaptic transmission in the hippocampus and cerebellum [5,6]. LTD is a process that, together with the opposite one, long-term potentiation has a great relevance for brain information storage and improvement of neurons links during development [7]. Furthermore, insulin receptor signaling regulates the maintenance of synapses and contributes to experience-dependent structural plasticity that is necessary for the recruitment of neurons into brain circuits [8]. Moreover, some studies suggest that insulin participates in neuronal differentiation of postnatal neural stem cell [9] and their culturing with both insulin and insulin-like growth factor (GF-1) causes a greater production of neurons during differentiation compared to culturesstimulated by IGF-1 alone [10].Insulin also avoids the necrosis of rat embryonic neurons cultured in a serum-free medium; in fact the protein was capable to restore the cell viability by activation of Protein Kinase C, having the crucial role of controlling other proteins ...

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Amyloid-β Induces Hepatic Insulin Resistance by Activating JAK2/STAT3/SOCS-1 Signaling Pathway

Cited by 91 publications

References 53 publications

Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

Suppressor of cytokine signalling (SOCS) proteins as guardians of inflammatory responses critical for regulating insulin sensitivity

Insulin Resistance: A Bridge between T2DM and Alzheimer’s Disease

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