Insulin deprivation decreases insulin degrading enzyme levels in primary cultured cortical neurons and in the cerebral cortex of rats with streptozotocin-induced diabetes

Kazkayası, İnci; Burul-Bozkurt, Nihan; Ismail, Muhammad-Al-Mustafa; Merino‐Serrais, Paula; Pekiner, Can; Cedazo-Minguez, Ángel; Shanmugasundaram, Uma

doi:10.1016/j.pharep.2018.01.008

Cited by 6 publications

(6 citation statements)

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“…Hyperglycaemia induced by STZ leads to progressive insulin resistance of the peripheral tissues, which results in mice being unresponsive to insulin [41]. Also, it has been reported that diabetes induced by STZ decreases IDE levels in the brains of rats [42]. Villa-Pérez et.al reported that liver-specific ablation of IDE leads to hepatic insulin resistance and glucose intolerance without affecting insulin clearance in mice [43].…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rb1 Improves Cognitive Impairment Induced by Insulin Resistance through Cdk5/p35-NMDAR-IDE Pathway

Yang

Jiang

et al. 2020

BioMed Research International

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The relationship between diabetes mellitus (DM) and Alzheimer’s disease (AD) has attracted wide attention. Studies have reported that ginsenoside Rb1 can improve human cognitive ability and glucose tolerance during the development of diabetes. The mechanism behind the improvement in cognitive ability and glucose tolerance still remains unclear. In this study, streptozotocin- (STZ-) injected mice were used as models to explore the mechanisms behind the cognitive improvement of ginsenoside Rb1. According to the results of behavioral tests, ginsenoside Rb1 improved memory and cognitive ability of STZ-lesioned mice. In addition to that, ginsenoside Rb1 also relieved glucose intolerance induced by STZ injection by enhancing insulin sensitivity. These beneficial effects of ginsenoside Rb1 is most likely mediated by upregulating the expression of NMDAR1 and IDE in the hippocampus through inhibiting the activity of Cdk5/p35. This work will be of great importance in illustrating the mechanisms of ginsenoside Rb1 for improving cognitive ability, as well as revealing the relationship between diabetes and AD.

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Section: Discussionmentioning

confidence: 99%

Ginsenoside Rb1 Improves Cognitive Impairment Induced by Insulin Resistance through Cdk5/p35-NMDAR-IDE Pathway

Yang

Jiang

et al. 2020

BioMed Research International

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“…There are data indicating that liver-specific ablation of insulindegrading enzyme causes hepatic insulin resistance and glucose intolerance (Villa-Perez et al 2018) and that pancreatic β-cell-specific deletion of insulindegrading enzyme leads to dysregulated insulin secretion (Fernandez-Diaz et al 2019). Furthermore, insulin deprivation in rats with streptozotocininduced diabetes down-regulates insulin degrading enzyme level in the cerebral cortex (Kazkayasi et al 2018). There are also data indicating that ablation of amyloid precursor protein (APP) increases insulindegrading enzyme levels and activity in brain and other tissues, which clearly demonstrate a novel role for APP as an upstream regulator of IDE in vivo and represents a new molecular link connecting APP to metabolic homeostasis (Kulas et al 2019).…”

mentioning

confidence: 99%

Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation

Minchenko

Khita

Tsymbal

et al. 2020

Endocrine Regulations

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Objective. The aim of the present investigation was to study the expression of genes encoding polyfunctional proteins insulinase (insulin degrading enzyme, IDE) and pitrilysin metallopeptidase 1 (PITRM1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of metabolism through ERN1 signaling as well as hypoxia, glucose and glutamine deprivations.Methods. The expression level of IDE and PITRM1 genes was studied in control and ERN1 knockdown U87 glioma cells under glucose and glutamine deprivations as well as hypoxia by quantitative polymerase chain reaction.Results. It was found that the expression level of IDE and PITRM1 genes was down-regulated in ERN1 knockdown (without ERN1 protein kinase and endoribonuclease activity) glioma cells in comparison with the control glioma cells, being more significant for PITRM1 gene. We also found up-regulation of microRNA MIR7-2 and MIRLET7A2, which have specific binding sites in 3’-untranslated region of IDE and PITRM1 mRNAs, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Only inhibition of ERN1 endoribonuclease did not change significantly the expression of IDE and PITRM1 genes in glioma cells. The expression of IDE and PITRM1 genes is preferentially regulated by ERN1 protein kinase. We also showed that hypoxia down-regulated the expression of IDE and PITRM1 genes and that knockdown of ERN1 signaling enzyme function modified the response of these gene expressions to hypoxia. Glucose deprivation increased the expression level of IDE and PITRM1 genes, but ERN1 knockdown enhanced only the effect of glucose deprivation on PITRM1 gene expression. Glutamine deprivation did not affect the expression of IDE gene in both types of glioma cells, but up-regulated PITRM1 gene and this up-regulation was stronger in ERN1 knockdown cells.Conclusions. Results of this investigation demonstrate that ERN1 knockdown significantly decreases the expression of IDE and PITRM1 genes by ERN1 protein kinase mediated mechanism. The expression of both studied genes was sensitive to hypoxia as well as glucose deprivation and dependent on ERN1 signaling in gene-specific manner. It is possible that the level of these genes expression under hypoxia and glucose deprivation is a result of complex interaction of variable endoplasmic reticulum stress related and unrelated regulatory factors and contributed to the control of the cell metabolism.

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“…However, the affinity of insulin for IDE is greater than Aβ, which means that insulin and Aβ will compete with each other for IDE. As a result, the occurrence of hyperinsulinemia may result in the accumulation of Aβ (Kazkayasi et al, 2018). Our results showed that the IDE expression of the hippocampus or cortex of HFD/STZ-induced T2DM rats was greater than the other groups, not only in line FIGURE 5 | Protein levels of PSD-95 in the hippocampus (A) and cortex (B), and BDNF levels in the hippocampus (C) and cortex (D) in high-fat diet and streptozotocin-induced type 2 diabetic rats treated with alpha-lipoic acid for 13 weeks.…”

Section: Discussionmentioning

confidence: 99%

Alleviative Effect of Alpha-Lipoic Acid on Cognitive Impairment in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats

et al. 2021

Front. Aging Neurosci.

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Background: The intricate relationship between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) suggests that insulin is involved in modulating AD-related proteins. Alpha-lipoic acid (ALA) can improve insulin resistance (IR) in diabetic rats. However, the role of ALA in alleviating the cognitive decline of T2DM is not yet clear. This study examined the ameliorative effect of ALA on cognitive impairment, cerebral IR, and synaptic plasticity abnormalities in high-fat diet (HFD) plus streptozotocin (STZ) induced diabetic rats.Methods: The HFD/STZ-induced T2DM male Wistar rats were orally administered with ALA (50, 100, or 200 mg/kg BW) once a day for 13 weeks. Abilities of cognition were measured with a passive avoidance test and Morris water maze. Specimens of blood and brain were collected for biochemical analysis after the rats were sacrificed. Western blotting was used to determine protein expressions in the hippocampus and cortex in the insulin signaling pathways, long-term potentiation (LTP), and synaptic plasticity-related protein expressions.Results: Alpha-lipoic acid improved hyperinsulinemia and the higher levels of free fatty acids of the T2DM rats. Behavioral experiments showed that the administration of ALA improved cognitive impairment in HFD/STZ-induced T2DM rats. ALA ameliorated insulin-related pathway proteins [phosphoinositide 3-kinase (PI3K), phospho-protein kinase B (pAkt)/Akt, and insulin-degrading enzyme (IDE)] and the LTP pathway, as well as synaptic plasticity proteins (calmodulin-dependent protein kinase II, cyclic AMP response element-binding protein, and postsynaptic density protein-95) of the cerebral cortex or hippocampus in HFD/STZ-induced T2DM rats.Conclusion: Our findings suggested that ALA may ameliorate cognition impairment via alleviating cerebral IR improvement and cerebral synaptic plasticity in diabetic rats.

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Insulin deprivation decreases insulin degrading enzyme levels in primary cultured cortical neurons and in the cerebral cortex of rats with streptozotocin-induced diabetes

Cited by 6 publications

References 41 publications

Ginsenoside Rb1 Improves Cognitive Impairment Induced by Insulin Resistance through Cdk5/p35-NMDAR-IDE Pathway

Ginsenoside Rb1 Improves Cognitive Impairment Induced by Insulin Resistance through Cdk5/p35-NMDAR-IDE Pathway

Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation

Alleviative Effect of Alpha-Lipoic Acid on Cognitive Impairment in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats

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