| Summary: | 博士 === 高雄醫學大學 === 醫學研究所博士班 === 92 === Background
Aerobic exercise including treadmill running has long been used to successfully treat and/or prevent insulin resistance and Type-2 diabetes. Increase of plasma b-endorphin is generally observed with exercise. Thus, the present study is designed to clarify the role of endogenous b-endorphin in exercise-induced improvement of insulin resistance.
Methods
Male obese Zucker rats aged 8 weeks were randomly assign to four groups; sedentary group (OS), exercise plus Vehicle group (E+V), exercise plus Naloxone group (E+N), exercise plus Naloxonazine group (E+NZ). Male lean Zucker rats that remained sedentary were control group (C). The moderate exercise program used in the present study is consisting of treadmill running at 20 m/ min and 0 % grade for 1 h/ day, 7 days /week, for 8 weeks. The plasma glucose concentration was assessed by glucose oxidase method. The enzyme-linked immunosorbent assay was performed to quantify the plasma level of b-endorphin-like immunoreactivity (BER). The glucose disposal rate (GDR) was measured by hyperinsulinemic euglycemic clamp technique. Changes of the insulin signaling in isolated soleus muscle were then detected by immunoprecipitation and immunoblotting.
In an attempt to prove the effect of b-endorphin on insulin resistance, Wistar rats fed fructose-rich chow was employed to induce insulin resistance. Changes of GDR were also measured using the hyperinsulinemic euglycemic clamp technique, in which b-endorphin (6 ng/kg/min) or vehicle were continued for 120 min. Then, soleus muscle was isolated to investigate the effect of b-endorphin on insulin signals.
Results
An increase of plasma BER in parallel with the reduction of plasma glucose was obtained in exercise-trained obese Zucker rat. Different to a marked reduction in sedentary obese Zucker rats, the value of insulin-stimulated GDR obtained from exercised obese Zucker rats was reversed to near that of sedentary lean group at 8 weeks later of the last exercise bout. This effect of exercise was inhibited by naloxone or naloxonazine at doses sufficient to block opioid m-receptors. The impaired glucose transporter subtype 4 (GLUT 4) transportations due to signaling defects including a lowered phosphorylation of insulin receptor substrate (IRS)-1, as well as an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation were observed in soleus muscle of sedentary obese Zucker rats. In contrast, exercise training failed to modify the levels of insulin receptor (IR) and IRS-1 as well as IR tyrosine autophosphorylation in obese Zucker rats.
A marked reduction of insulin-stimulated GDR was also observed in fructose-fed rats compared with normal control. Infusion of b-endorphin reversed the value of GDR that was inhibited by naloxone or naloxonazine at doses sufficient to block opioid m-receptors. Activation of opioid m-receptors by b-endorphin to improve insulin resistance can thus be considered.
The insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease of IRS-1 tyrosine phosphorylation in the soleus muscle. The impaired glucose transportation was also due to signaling defects, which included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, the IR protein level was not markedly changed in rats with insulin resistance. Infusion of b-endorphin reversed the fructose-induced decrement in the insulin-signaling cascade with the raise of GDR value. The change of insulin signsls was the same as that produced by exercise teaining.
Conclusion
The improvement of insulin resistance by exercise training appears to be mediated by endogenous b-endorphin through an increase of post-receptor insulin signaling related to the IRS-1-associated PI3-kinase step that leads to enhance of GLUT 4 translocation and improve glucose disposal in obese Zucker rats. This view is further supported by the infusion of b-endorphin in gructode-fed rats with insulin resistance.
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