Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

doi:10.1007/s12264-016-0034-9

Cited by 26 publications

(23 citation statements)

References 64 publications

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“…The crosstalk between cholesterol dysmetabolism and IR is bidirectional: not only hypercholesterolemia and altered cholesterol homeostasis affect IR, but also IR may, conversely, affect cholesterol metabolism; in fact, insulin can activate the transcription factors SREBPs involved in cholesterol biosynthesis (Suzuki et al, 2010). In addition, insulin increases cholesterol biosynthesis in SH-SY5Y and N2a cells, by upregulating 24-dehydrocholesterol reductase, and HMG-CoA reductase through SREBP2, whereas Aβ-induced IR leads to dysregulation of cholesterol homeostasis (Najem et al, 2016). Moreover, insulin-deficient diabetes leads to a reduced cholesterol synthesis in the brain due to lower expression of SREBP2 and of its downstream genes in the hypothalamus and in other brain regions, resulting in altered synaptic formation, and function (Suzuki et al, 2010, 2013).…”

Section: The Interplay Between Cholesterol and Glucose Metabolism In mentioning

confidence: 99%

A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

et al. 2019

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In Alzheimer’s disease (AD), both cholesterol and glucose dysmetabolism precede the onset of memory deficit and contribute to the disease’s progression. It is indeed now believed that oxidized cholesterol in the form of oxysterols and altered glucose uptake are the main triggers in AD affecting production and clearance of Aβ, and tau phosphorylation. However, only a few studies highlight the relationship between them, suggesting the importance of further extensive studies on this topic. Recently, a molecular link was demonstrated between cholesterol oxidative metabolism and glucose uptake in the brain. In particular, 27-hydroxycholesterol, a key linker between hypercholesterolemia and the increased AD risk, is considered a biomarker for reduced glucose metabolism. In fact, its excess increases the activity of the renin-angiotensin system in the brain, thus reducing insulin-mediated glucose uptake, which has a major impact on brain functioning. Despite this important evidence regarding the role of 27-hydroxycholesterol in regulating glucose uptake by neurons, the involvement of other cholesterol oxidation products that have been clearly demonstrated to be key players in AD cannot be ruled out. This review highlights the current understanding of the potential role of cholesterol and glucose dysmetabolism in AD progression, and the bidirectional crosstalk between these two phenomena.

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Section: The Interplay Between Cholesterol and Glucose Metabolism In mentioning

confidence: 99%

A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

et al. 2019

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“…In recent years, both insulin and C-peptide (a peptide cleaved from proinsulin and eventually released into the bloodstream in amounts equimolar with those of insulin) have been shown to exert various influences on anti-apoptosis, metabolic diseases, and nervous system diseases [ 4 – 7 ]. The deterioration of β-cell function has been demonstrated to be associated with diabetic complications [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Decreased β-Cell Function is Associated with Cardiovascular Autonomic Neuropathy in Chinese Patients Newly Diagnosed with Type 2 Diabetes

Yang

Zhu

et al. 2018

Neurosci. Bull.

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The influence of β-cell function on cardiovascular autonomic neuropathy (CAN), an important diabetes-related complication, is still unclear. In this study, we aimed to investigate the association between residual β-cell function and CAN in patients newly diagnosed with type 2 diabetes. We enrolled 90 newly-diagnosed type 2 diabetic patients and 37 participants with normal glucose tolerance as controls. The patients were divided into a CAN+ group (diabetic patients with CAN, n = 20) and a CAN− group (diabetic patients without CAN, n = 70) according to the standard Ewing battery of tests. Fasting and postprandial plasma glucose, insulin, and C-peptide were measured. Homeostasis model assessment-beta cells (HOMA-B) and HOMA-insulin resistance (IR) were calculated. The prevalence of CAN in this population was 22.2%. Compared with the CAN− group, the CAN+ group had significantly lower fasting plasma insulin (6.60 ± 4.39 vs 10.45 ± 7.82 μ/L, P = 0.029), fasting C-peptide (0.51 ± 0.20 vs 0.82 ± 0.51 nmol/L, P = 0.004), and HOMA-B (21.44 ± 17.06 vs 44.17 ± 38.49, P = 0.002). Fasting C-peptide was correlated with the Valsalva ratio (r = 0.24, P = 0.043) and the 30:15 test (r = 0.26, P = 0.023). Further analysis showed that fasting C-peptide (OR: 0.041, 95% CI 0.003–0.501, P = 0.012) and HOMA-B (OR: 0.965, 95% CI 0.934–0.996, P = 0.028) were independently associated with cardiovascular autonomic nerve function in this population. The patients with fasting C-peptide values < 0.67 nmol/L were more likely to have CAN than those with C-peptide levels ≥0.67 nmol/L (OR: 6.00, 95% CI 1.815–19.830, P = 0.003). A high prevalence of CAN was found in patients with newly-diagnosed type 2 diabetes. Decreased β-cell function was closely associated with CAN in this population.

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“…On the other hand, Ab has also been found to modulate insulin signaling. For example, Ab can reduce the responsiveness to insulin in presynaptic terminals (Heras-Sandoval et al, 2012), decrease insulin expression in cultured astrocytes (Takano et al, 2018), impair neuronal insulin receptors (Zhao et al, 2008), and induce insulin resistance in neuronal cells and peripheral cells (Zhang et al, 2012;Najem et al, 2016;Wani et al, 2019). These deleterious effects of Ab on insulin action or insulin sensitivity may be mediated by activating the JAK2/STAT3/SOCS-1 or JNK signaling pathways (Zhang et al, 2012;Najem et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…To observe the potential effects of icariin on neuronal insulin resistance, human neuroblastoma SK-N-MC cells were serumstarved for 6 h and then treated with or without 2.5 mM of Ab 1-42, in the presence or absence of 25, 50, or 100 mM of icariin for 24 h, followed by stimulation with or without 100 nM of insulin for 10 min. Ab was used to induce neuronal insulin resistance in vitro (Zhao et al, 2008;Najem et al, 2016;Sajan et al, 2016;Wani et al, 2019) and insulin was administered to stimulate insulin signaling. As shown in Figure 1, icariin treatment reversed the inhibitory effects of Ab on insulin-stimulated phosphorylation of Akt at Thr308 and of its downstream substrate AS160 ( Figures 1A, B).…”

Section: Icariin Improved Ab-induced Neuronal Insulin Resistancementioning

confidence: 99%

Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation

Zou

Feng

et al. 2020

Front. Pharmacol.

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Neuronal insulin resistance is implicated in neurodegenerative diseases. Icariin has been reported to improve insulin resistance in skeletal muscle cells and to restore impaired hypothalamic insulin signaling in the rats with chronic unpredictable mild stress. In addition, icariin can exert the neuroprotective effects in the mouse models of neurodegenerative diseases. However, the molecular mechanisms by which icariin affects neuronal insulin resistance are poorly understood. In the present study, amyloid-b (Ab) was used to induce insulin resistance in human neuroblastoma SK-N-MC cells. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt T308 phosphorylation and glucose uptake. We found that the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mediated Ab-induced insulin resistance. Icariin treatment markedly reduced Ab-enhanced PTEN protein levels, leading to an improvement in Abinduced insulin resistance. Accordingly, PTEN overexpression obviously abolished the protective effects of icariin on Ab-induced insulin resistance. Furthermore, icariin activated proteasome activity. The proteasome inhibitor MG132 attenuated the effects of icariin on PTEN protein levels. Taken together, these results suggest that icariin protects SK-N-MC cells against Ab-induced insulin resistance by activating the proteasome-dependent degradation of PTEN. These findings provide an experimental background for the identification of novel molecular targets of icariin, which may help in the development of alternative therapeutic approaches for neurodegenerative diseases.

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Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

Abstract: Alzheimer's disease (AD) is characterized by amyloid-b (Ab) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration.

Cited by 26 publications

References 64 publications

A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

Decreased β-Cell Function is Associated with Cardiovascular Autonomic Neuropathy in Chinese Patients Newly Diagnosed with Type 2 Diabetes

Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation

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