||The merit of hyperbaic oxygen therapy in diabetic rats
||Department of Pharmacology
hyperbaric oxygen therapy
所謂高壓氧治療 (hyperbaric oxygen therapy, HBOT)，即藉由提高氧分壓，促使更多的氧氣溶入血液循環中。並且，在臨床上常用於解決傷口創傷等問題，其中包括糖尿病人易發生的糖尿病足。先前文獻指出，人體暴露在高壓氧環境下，體內β-腦內啡 (β-endorphin)的量會有明顯增加的情況。此外，β-腦內啡具有調節體內醣類恆定的作用。然而，高壓氧治療是否會藉由促進β-腦內啡釋放增加進而調節醣類恆定目前仍不清楚。本實驗結果發現，STZ (streptozocin)誘導之第一型糖尿病鼠在高壓氧治療之下，其體內β-腦內啡是增加的，且其原本在高壓氧治療之下所導致的降血糖作用，可以藉由前處理嗎啡受體拮抗劑naloxone或嗎啡μ型受體拮抗劑naloxonazine達到抑制的作用。這些結果指出高壓氧治療可以藉由提高體內β-腦內啡的表現，進而活化嗎啡μ型受體而達到降低血糖的作用。接著，結果發現，在前處理NMDA接受體拮抗劑MK801或菸鹼受體拮抗劑hexmethonium後，可以抑制高壓氧治療所產生的降血糖作用及β-腦內啡增加的現象，且去除腎上腺第一型糖尿病鼠或糖尿病鼠經脊髓截斷手術後，在高壓氧治療後，也看到同樣的抑制效果。此結果可以得知，高壓氧治療可以藉由中樞NMDA接受體活化所產生的神經傳遞作用，促進腎上腺髓質菸鹼受體活化，進而促使β-腦內啡分泌，達到降血糖的作用。另一方面，已知β-腦內啡可以改變骨骼肌葡萄醣轉運蛋白 (glucose transport type 4, GLUT4)的表現促使葡萄糖的攝入增加，其也可以促進肝臟肝醣的合成並抑制肝臟中的磷酸烯醇式丙酮酸羧激 (phosphoenolpyruvatecarboxykinase, PEPCK)，降低醣質新生作用，故有調節醣類恆定與降低血糖的作用。肝臟中蛋白質激C ζ (protein kinase C ζ, PKCζ)的活化可以抑制肝醣合成激-3β(glycogen synthase kinase 3β, GSK3β)，故有促進肝醣合成的作用。從實驗結果發現，糖尿病鼠在經三天的高壓氧治療後，其骨骼肌膜上蛋白GLUT4表現有增加的情形，肝臟中PEPCK的表現是降低的，且肝臟中的PKCζ及GSK3β磷酸化有增加的現象，以及肝醣的堆積有增加的情況。這些結果皆可以藉由前處理嗎啡μ型受體拮抗劑naloxonazine而受到抑制。綜合以上結果，本研究發現，高壓氧治療藉由β-腦內啡的釋放有助於第一型糖尿病鼠改善醣類恆定。
Hyperbaric oxygen therapy (HBOT) was defined as a treatment that made more oxygen dissolved in blood circulation by raising the partial pressure of oxygen, and was usually used to deal with wound problems including diabetic foot ulcer. Previous study indicates that plasma β-endorphin was increased in human after acute hyperbaric oxygen exposure. β-Endorphin is known to regulate glucose homeostasis. Howerver, whether HBOT regulates glucose homeostasis through β-endorphin release is still obscure. In the present study, we found that HBOT increased plasma β-endorphin release in streptozocin (STZ) diabetic rats. Moreover, HBOT exerted a blood glucose-lowering action, which was recovered by naloxone or naloxonazine pretreatment. These results indicated that decreased blood glucose induced by HBOT was through β-endorphin release to activate opioid μ-receptor. The decrease of blood glucose and β-endorphin increment in HBOT-treated STZ diabetic rats were also suppressed by pretreatment with MK801 (NMDA receptor antagonist) and hexamethonium (nicotinic receptor antagonist), as well as adrenalectomy and spinal cord truncation. Thus, the obtained data suggest that HBOT might activate NMDA neurotransmission in brain to increase β-endorphin release from adrenal gland through an activation of nicotinic neurotransmission. On the other hand, β-endorphin is known to not only raise glucose transport type 4 (GLUT4) expression to increase glucose uptake in skeletal muscle, but also decrease phosphoenolpyruvatecarboxykinase (PEPCK) expression to reduce gluconeogenesis in liver. β-Endorphin also promotes hepatic glycogen synthesis. Activation of protein kinase C ζ (PKCζ) inhibits glycogen synthase kinase 3β (GSK3β) activity to increase hepatic glycogen synthesis. In our study, STZ diabetic rats after received HBOT for three days had elevated membrane Glut4 and lowered PEPCK expression, as well as increased phosorylation of PKC ζ and GSK3β and glycogen content, which were all reversed by naloxonazine. Taken together, we found, at least in part, HBOT had benefits for diabetic care in STZ diabetic rats through β-endorphin release to improve glucose homeostasis.
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