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, 217 (2), 175-84

Acute Psychological Stress Results in the Rapid Development of Insulin Resistance

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Acute Psychological Stress Results in the Rapid Development of Insulin Resistance

Li Li et al. J Endocrinol.

Abstract

In recent years, the roles of chronic stress and depression as independent risk factors for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding of the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES) followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared with normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue, and brain. Additionally, a rise in the murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism.

Figures

Figure 1
Figure 1. Inescapable foot shocks (IES)-induced behavioral changes in mice
(A) Animal groups included in the study and different treatments. (B) Schedule for the IES training, escape test, blood and tissue collection, and insulin/glucose tolerance tests. (C and D) Mice were tested for behavioral changes, which was assessed by calculating escape latency and escape failure. Mice that were exposed to IES and had 15 or more than 15 out of the 30 escape trials were IES with escape failure group (IES+EF), had less than 15 out of the 30 escape trials were IES without escape failure group (IES−EF). There are 16 mice in sham group, 4 mice in IES without escape failure group (IES−EF group) and 20 mice in IES with escape failure group (IES+EF group).
Figure 1
Figure 1. Inescapable foot shocks (IES)-induced behavioral changes in mice
(A) Animal groups included in the study and different treatments. (B) Schedule for the IES training, escape test, blood and tissue collection, and insulin/glucose tolerance tests. (C and D) Mice were tested for behavioral changes, which was assessed by calculating escape latency and escape failure. Mice that were exposed to IES and had 15 or more than 15 out of the 30 escape trials were IES with escape failure group (IES+EF), had less than 15 out of the 30 escape trials were IES without escape failure group (IES−EF). There are 16 mice in sham group, 4 mice in IES without escape failure group (IES−EF group) and 20 mice in IES with escape failure group (IES+EF group).
Figure 2
Figure 2. Decreased insulin signaling following acute psychological stress in the liver
Mice that were not exposed to IES but had escape test are sham group (sham). At the end of the behavioral test, 5U/kg insulin was administered via intraperitoneal injection and the liver was removed 20 min after the insulin injection. Tissue lysates, 30 μg per lane, were subjected to Western blot analysis with antibodies specific for phospho-serine (PS) 473-AKT, phospho-threonine (PT) 308-AKT, total AKT, phospho-tyrosine (PY)-IRS1, total IRS1, PY-IR, or total IR. Representative Western blots are presented in A, C, E and G. (B, D, F and H) Autoradiographs from different groups (corresponding to A, C, E and G, respectively) were quantified by scanning densitometry. The data are presented as the mean ± S.E of 4 mice in IES without escape failure group (IES-EF group), 10 mice in IES with escape failure group (IES+EF group) and 10 mice in sham group. The phosphorylated protein levels in the sham group were arbitrarily set to 100%. White gap in A, C, E and G indicates grouping of lanes from different parts of the same gel.
Figure 2
Figure 2. Decreased insulin signaling following acute psychological stress in the liver
Mice that were not exposed to IES but had escape test are sham group (sham). At the end of the behavioral test, 5U/kg insulin was administered via intraperitoneal injection and the liver was removed 20 min after the insulin injection. Tissue lysates, 30 μg per lane, were subjected to Western blot analysis with antibodies specific for phospho-serine (PS) 473-AKT, phospho-threonine (PT) 308-AKT, total AKT, phospho-tyrosine (PY)-IRS1, total IRS1, PY-IR, or total IR. Representative Western blots are presented in A, C, E and G. (B, D, F and H) Autoradiographs from different groups (corresponding to A, C, E and G, respectively) were quantified by scanning densitometry. The data are presented as the mean ± S.E of 4 mice in IES without escape failure group (IES-EF group), 10 mice in IES with escape failure group (IES+EF group) and 10 mice in sham group. The phosphorylated protein levels in the sham group were arbitrarily set to 100%. White gap in A, C, E and G indicates grouping of lanes from different parts of the same gel.
Figure 3
Figure 3. Insulin-induced phosphorylation of AKT was not affected by acute psychological stress in skeletal muscle and adipose tissue
At the end of the behavioral test, 5U/kg insulin was injected and skeletal muscle and adipose tissue were removed 20 min after injection. Tissue lysates, 30 μg per lane, were subjected to Western blotting with antibodies specific for PS473-AKT or total ERK. Representative Western blots are presented in A and C. (B and D) Autoradiographs were quantified by scanning densitometry and the data are presented as the mean ± S.E of 10 mice in IES with escape failure group (IES+EF group) and 10 mice in sham group. The phosphorylated protein level in the sham group was arbitrarily set to 100%. White gap in A and C indicates grouping of lanes from different parts of the same gel.
Figure 4
Figure 4. Effects of acute psychological stress on the insulin signaling in central nervous system
At the end of the behavioral test, 5U/kg insulin was injected and 20 min later the hypothalamus, hippocampus and amygdala were removed. Tissue lysates, 20 μg per lane, were subjected to Western blot analysis with antibodies specific for PS473-AKT or total ERK. There were 10 mice in IES with escape failure group (IES+EF group) and 10 mice in sham group. Representative Western blots are presented in A, B and C. White gap in A, B and C indicates grouping of lanes from different parts of the same gel.
Figure 5
Figure 5. Effects of acute psychological stress on insulin sensitivity and glucose disposal
(A) Mice were fasted 4 h for insulin sensitivity tests and 2U/kg insulin was administered through intraperitoneal injection. (C) For glucose tolerance tests, mice were fasted 16 h and 1g/kg glucose was administered through intraperitoneal injection. Data are presented as the mean ± S.E in each group. (B and D) Bar graphs of the area under the curve of blood glucose levels in insulin tolerance tests and glucose tolerance tests, respectively. Animal numbers in each group were indicated in the figures. IES+EF, IES with escape failure group.
Figure 6
Figure 6. Plasma levels of inflammatory cytokines and corticosterone
The mice were sacrificed at the end of the escape test and blood was collected for the determination of plasma inflammatory markers levels and corticosterone levels. Each value represents the mean ± S.E of 10 mice in IES with escape failure group (IES+EF group) and 10 mice in sham group.

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