Control of post-ischemic hyperglycemia with Interleukin-13 by inhibiting metabolic pro-inflammatory state and insulin resistance in permanent cerebral ischemia rat model

腦中風為全世界死亡原因的前三名，而高血糖又被認為是中風預後的危險因子。然而，臨床調查顯示，即使是先前沒有糖尿病相關病史的急性腦中風患者，約有8-65%的患者會在中風後發生潛在糖尿病或葡萄糖耐受不良的高血糖，可能造成患者預後不佳、死亡率較高或神經復原較差。但是，缺血性腦中風後高血糖的發生機制還不甚了解，對於中風患者的血糖控制也尚無一個可以依循的準則。臨床上目前仍是使用胰島素在控制缺血性中風後高血糖，然而治療的效果仍有正反兩面的爭議。另外，有研究顯示腦中風會釋放反調節激素、前炎症細胞激素等調節激素，會促進糖質新生作用降低胰島素路徑的敏感性導致胰島素阻抗。而由輔助型T2淋巴細胞所分泌的介白素13(interleukin-13；簡寫為IL-13)為抑炎症細胞素家族的一種，在體內試驗被證實有促進胰島素路徑的敏感性及抑制肝臟糖質新生的作用，過量表現IL-13可以改善肥胖造成的葡萄糖代謝異常及胰島素阻抗。因此本研究欲透過永久性缺血性腦中風的大鼠模式，探討缺血性腦中風後高血糖的發生機制以及細胞素IL-13可能扮演的角色。結果顯示腦中風會造成高血糖、高胰島素血症、胰島素阻抗、胰島素路徑被抑制及糖質新生增加，且有系統性前炎症細胞素增加、抑炎症細胞素減少的情形。而IL-13能有效反轉上述腦中風所造成的病理變化，應與其活化JAK1/STAT6的細胞素路徑，改變炎症傾向有關。我們的研究結果顯示，IL-13治療可能可以作為中風後高血糖症的預防和控制新方針。Cerebral ischemia (stoke) is one of the leading causes of death and disability worldwide, whereas hyperglycemia is known as a risk factor for stroke prognosis. Post-ischemic hyperglycemia happens to about 8-63% acute ischemic stroke patients even without preexisting diabetes, which might cause poor prognosis, higher mortality, and impaired neurological recovery. However, with the unknown mechanism, there has not been a protocol for treating post-ischemic hyperglycemia. On the other hand, research found that acute stroke secretes counter-regulatory hormones, pro-inflammatory cytokines, and other regulatory factors, which enhances insulin resistance. Interleukin-13 (IL-13), as a member of the Th2 anti-inflammatory cytokine family, was reported to be involved in glucose hemostasis. Studies showed that IL-13 is capable of enhancing insulin sensitivity and suppressing hepatic gluconeogenesis, and that overexpressing IL-13 reverses abnormal glucose metabolism and insulin resistance in obese mice. Thus, we aim to discuss the mechanism of post-ischemic hyperglycemia and the role IL-13 may play in this phenomena through permanent middle artery occlusion rat model. Our results showed that post-ischemic hyperglycemia was accompanied by elevated insulin resistance index, elevated serum insulin concentration, elevated hepatic gluconeogenesis, and decreased insulin signaling. Meanwhile, systemic pro-inflammatory cytokine was also found significantly elevated and anti-inflammatory cytokine decreased. With IL-13 treatment, the above pathological state was reversed due to the JAK1/STAT6 signaling activation, which shifted the inflammatory state towards Th2 immunity. Our findings suggest that IL-13 treatment may be a new perspective for the prevention and control of post-ischemic hyperglycemia.1. Introduction and paper review…………………………………………………1 2. Materials and Methods…………………………………………………………10 3. Results…………………………………………………………………………14 4. Discussion……………………………………………………………………25 5. References……………………………………………………………………3