Robust adaptation of PKCζ-IRS1 insulin signaling pathways through integral feedback control.

Insulin signaling pathways in muscle tissue play a major role in maintaining glucose homeostasis. Dysregulation in these pathways results in the onset of serious metabolic disorders like type 2 diabetes. Robustness is an essential characteristic of insulin signaling pathways that ensures reliable signal transduction in the presence of perturbations as a result of several feedback mechanisms. Integral control, according to control engineering, provides reliable setpoint tracking and disturbance rejection. The presence of negative feedback and integrating process is crucial for biological processes to achieve integral control. The existence of an integral controller leads to the rejection of perturbations which resulted in the robust regulation of biochemical entities within acceptable levels. In the presentin silicoresearch work, the presence of integral control in the protein kinase Cζ- insulin receptor substrate-1 (PKCζ-IRS1) pathway is identified, verified mathematically and model is simulated in Cell Designer. The data is exported to Minitab software and robustness analysis is carried out statistically using the Mann-Whitney test. The p-value of the results obtained with given parameters perturbed by ±1% is greater than the significance level of 0.05 (0.2132 for 1% error in k7(rate constant of IRS1 phosphorylation), 0.2096 for -1% error in k7, 0.9037 for both ±1% error in insulin and 0.9037 for ±1% error in k1(association rate constant of the first molecule of insulin to bind the insulin receptor), indicated that our hypothesis is proved The results satisfactorily indicate that even when perturbations are present, glucose homeostasis in muscle tissue is robust due to the presence of integral regulation in the PKCζ-IRS1 insulin signaling pathways. In this paper, we have analysed the findings from the framework of robust control theory, which has allowed us to examine that how PKCζ-IRS1 insulin signaling pathways produces desired output in presence of perturbations.

Intranasal insulin administration may be highly effective in improving cognitive function in mice with cognitive dysfunction by reversing brain insulin resistance.

It is well known in clinical practice that Alzheimer's disease (AD) is closely associated with brain insulin resistance, and the cerebral insulin pathway has been proven to play a critical role in the pathogenesis of AD. However, finding the most efficient way to improve brain insulin resistance remains challenging. Peripheral administration of insulin does not have the desired therapeutic effect and may induce adverse reactions, such as hyperinsulinemia, but intranasal administration may be an efficient way. In the present study, we established a brain insulin resistance model through an intraventricular injection of streptozotocin, accompanied by cognitive impairment. Following intranasal insulin treatment, the learning and memory functions of mice were significantly restored, the neurogenesis in the hippocampus was improved, the level of insulin in the brain increased, and the activation of the IRS-1-PI3K-Akt-GSK3ß insulin signal pathway, but not the Ras-Raf-MEK-MAPK pathway, was markedly increased. The olfactory bulb-subventricular zone-subgranular zone (OB-SVZ-SGZ) axis might be the mechanism through which intranasal insulin regulates cognition in brain-insulin-resistant mice. Thus, intranasal insulin administration may be a highly efficient way to improve cognitive function by increasing cerebral insulin levels and reversing insulin resistance.

The effect of noise exposure on insulin sensitivity in mice may be mediated by the JNK/IRS1 pathway.

BACKGROUND: Epidemiological studies have suggested that noise exposure may increase the risk of type 2 diabetes mellitus (T2DM), and experimental studies have demonstrated that noise exposure can induce insulin resistance in rodents. The aim of the present study was to explore noise-induced processes underlying impaired insulin sensitivity in mice. METHODS: Male ICR mice were randomly divided into four groups: a control group without noise exposure and three noise groups exposed to white noise at a 95-dB sound pressure level for 4 h/day for 1, 10, or 20 days (N1D, N10D, and N20D, respectively). Systemic insulin sensitivity was evaluated at 1 day, 1 week, and 1 month post-noise exposure (1DPN, 1WPN, and 1MPN) via insulin tolerance tests (ITTs). Several insulin-related processes, including the phosphorylation of Akt, IRS1, and JNK in the animals' skeletal muscles, were examined using standard immunoblots. Biomarkers of inflammation (circulating levels of TNF-α and IL-6) and oxidative stress (SOD and CAT activities and MDA levels in skeletal muscles) were measured via chemical analyses. RESULTS: The data obtained in this study showed the following: (1) The impairment of systemic insulin sensitivity was transient in the N1D group but prolonged in the N10D and N20D groups. (2) Noise exposure led to enhanced JNK phosphorylation and IRS1 serine phosphorylation as well as reduced Akt phosphorylation in skeletal muscles in response to exogenous insulin stimulation. (3) Plasma levels of TNF-α and IL-6, CAT activity, and MDA concentrations in skeletal muscles were elevated after 20 days of noise exposure. CONCLUSIONS: Impaired insulin sensitivity in noise-exposed mice might be mediated by an enhancement of the JNK/IRS1 pathway. Inflammation and oxidative stress might contribute to insulin resistance after chronic noise exposure.

The effect of noise exposure on insulin sensitivity in mice may be mediated by the JNK/IRS1 pathway

BACKGROUND@#Epidemiological studies have suggested that noise exposure may increase the risk of type 2 diabetes mellitus (T2DM), and experimental studies have demonstrated that noise exposure can induce insulin resistance in rodents. The aim of the present study was to explore noise-induced processes underlying impaired insulin sensitivity in mice.@*METHODS@#Male ICR mice were randomly divided into four groups: a control group without noise exposure and three noise groups exposed to white noise at a 95-dB sound pressure level for 4 h/day for 1, 10, or 20 days (N1D, N10D, and N20D, respectively). Systemic insulin sensitivity was evaluated at 1 day, 1 week, and 1 month post-noise exposure (1DPN, 1WPN, and 1MPN) via insulin tolerance tests (ITTs). Several insulin-related processes, including the phosphorylation of Akt, IRS1, and JNK in the animals' skeletal muscles, were examined using standard immunoblots. Biomarkers of inflammation (circulating levels of TNF-α and IL-6) and oxidative stress (SOD and CAT activities and MDA levels in skeletal muscles) were measured via chemical analyses.@*RESULTS@#The data obtained in this study showed the following: (1) The impairment of systemic insulin sensitivity was transient in the N1D group but prolonged in the N10D and N20D groups. (2) Noise exposure led to enhanced JNK phosphorylation and IRS1 serine phosphorylation as well as reduced Akt phosphorylation in skeletal muscles in response to exogenous insulin stimulation. (3) Plasma levels of TNF-α and IL-6, CAT activity, and MDA concentrations in skeletal muscles were elevated after 20 days of noise exposure.@*CONCLUSIONS@#Impaired insulin sensitivity in noise-exposed mice might be mediated by an enhancement of the JNK/IRS1 pathway. Inflammation and oxidative stress might contribute to insulin resistance after chronic noise exposure.

Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2.

The occurrence of an inherent or acquired resistance to temozolomide (TMZ) is a major burden for patients suffering from glioma. Recently, studies have demonstrated that microRNAs play an important role in the regulation of tumor properties in cancers. However, whether miR-497 contributes to glioma resistance to chemotherapy is not fully understood. In this study, we showed that the expression of miR-497 was markedly up-regulated in TMZ-resistant glioma cells; high miR-497 expression level was associated with TMZ-resistant phenotype of glioma cells. The down-regulation of miR-497 in glioma cells enhanced the apoptosis-induction and growth inhibition effects of TMZ both in vitro and in vivo, whereas promotion of miR-497 increased the chemosensitization of glioma cells to TMZ. The increased level of miR-497 in TMZ-resistant glioma cells was concurrent with the up-regulation of insulin-like growth factor 1 receptor (IGF1R)/insulin receptor substrate 1 (IRS1) pathway-related proteins, that is, IGF1R, IRS1, mammalian target of rapamycin (mTOR), and Bcl-2. In addition, the knockdown of mTOR and Bcl-2 reduced the tolerance of glioma cells to TMZ. Our results demonstrated that overexpression of miR-497 is significantly correlated with TMZ resistance in glioma cells by regulating the IGF1R/IRS1 pathway. Therefore, miR-497 may be used as a new target for treatment of chemotherapy-resistant glioma.