胰島素抗阻(insulin resistance)是形成第二型糖尿病的主要原因。過去文獻指出，肥胖(obesity)會導致增大的脂肪組織釋放出發炎激素，而使生物體處於一個慢性發炎的狀態，進一步促使胰島素抗阻的發生。然而，胰島素抗阻是否可以在沒有肥胖的狀況下產生，仍然不清楚。因此我們利用一個在脂肪組織，以棉球引發的肉芽腫(cotton pellet granuloma; CPG)非肥胖型發炎動物模式，來評估胰島素抗阻的產生。我們發現在附睪附近的白色脂肪(epididymal white adipose tissue)而非肩頰骨間的棕色脂肪 (interscapular brown adipose tissue)，植入棉球後，會降低胰島素敏感性及葡萄糖利用率，而在骨骼肌和肝臟的磷酸化胰島素受體(phosphoinsulin receptor)及Akt也會減低。在脂肪組織中的巨噬細胞(macrophage)浸潤情形、血液中白血球數量、單核球化學引誘蛋白 (monocyte chemoattractant protein)-1以及介白素(interleukin-6)的量，在棉球植入後的小鼠體內都有明顯的增加。然而，我們發現在附睪白色脂肪植入棉球的小鼠，其血中的脂聯素(adiponectin)含量是比較低的，而此一現象可能是因為在白色脂肪中，加瑪型脂小體增生活化受體(peroxisome proliferator-activated receptor-gamma;PPARgamma表現量降低的緣故。此外我們也發現非類固醇性消炎劑indomethacin能夠藉由增加PPARgamma的表現而降低血液中一氧化氮產物(nitrate/nitrite)和前列腺素E2prostaglandin)的含量，進一步改善胰島素抗阻。因此，肥胖並非是造成胰島素抗阻產生的必要條件，而在白色脂肪的發炎現象，對於胰島素抗阻的發生，扮演了一個重要的角色。此外，消炎藥物也許可以做為一個治療糖尿病的選擇。
除了肥胖之外，雖然過去普遍認為脂肪肝(hepatic steatosis) 與胰島素抗阻的形成也是息息相關的，然而兩者的關聯性仍然存在著矛盾關係。 本研究利用人類肝臟腫瘤細胞Hep G2 投予油酸(oleic acid)處理後，發現細胞內的中性脂肪酸有明顯堆積增加的現象，卻沒有觀察到胰島素抗阻的產生。此外，我們發現油酸可以藉由一個鈣離子依賴的路徑，增加peroxisome proliferator-activated receptor-delta;PPARdelta的表現，而PPARdelta可以藉由抑制PTEN的表現，增加胰島素的敏感性。進一步在Hep G2細胞中將PPARdelta剔除後，可以發現在油酸的處理下，細胞內中性脂肪酸的堆積有顯著增加的現象，同時也可以觀察到胰島素抗阻的發生。此外，投予PPARdelta致效劑於由高脂飲食所引致之第二型糖尿病鼠，不但可以顯著地改善脂肪肝，同時也可以改善胰島素抗阻。綜合以上，我們發現脂肪肝的產生不ㄧ定會造成胰島素抗阻，而PPARdelta對於脂肪肝所造成的胰島素抗阻扮演一個關鍵角色。
總結以上，我們發現活化PPAR家族不只能抑制發炎反應，同時亦能增加胰島素敏感度。因此，開發PPAR致效劑是一個治療糖尿病的重要策略。

Insulin resistance is the major risk for the development of type 2 diabetes. Obesity leads larger adipocytes secrete proinflammatory cytokines that cause chronic inflammation in animals. This, in turn, leads to the development of insulin resistance (IR). However, the development of IR without obesity is still obscure. We aimed to use a non-obese animal model with inflammation by cotton pellet granuloma transplantation (CPG) in adipose tissue to characterize IR development. We found that CPG in epididymal white adipose tissue (WAT), rather than in interscapular brown adipose tissue, impaired insulin sensitivity, and glucose utilization, and that it decreased levels of phospho-insulin receptor and phospho-Akt in both muscle and liver tissue. Macrophage infiltration in adipose tissue, leukocyte counts, monocyte chemoattractant protein-1, and interleukin-6 were elevated in CPG-treated mice. However, we found a marked decrease of plasma adiponectin only in the WAT group, which might have been because of the decreased level of peroxisome proliferator-activated receptor-gamma(PPARgamma)in WAT. In addition, we also found that indomethacin, a non-steroidal anti-inflammatory drug, might elevate the expression of PPARgamma to decrease serum nitrate/nitrite andprostaglandin E2 levels. These effects further led to the improvement of IR. Therefore, obesity itself is not an essential factor for IR and inflammation plays a crucial role in the development of IR. In addition, anti-inflammatory drugs might be applied as candidates for diabetes therapy.
It was widely believed that the development of IR is associated with hepatic steatosis. This concept is however subject to controversy, with recent studies indicating that fatty liver is not always associated with IR and that IR is not a critical factor in the development of hepatic steatosis. In this study, oleic acid induced steatosis in HepG2 cells with normal insulin sensitivity in consistent with the previous study. Moreover, oleic acid increased the expression of PPARdelta through a calcium-dependent pathway, and the increase of PPARdelta expression further decreased the expression of phosphatase and tensin homolog (PTEN) to increase insulin sensitivity. Knockdown of peroxisome proliferator-activated receptor-delta (PPARdelta) not only augmented the development of lipid accumulation in HepG2 cells but also impaired insulin sensitivity. In addition, administration of PPARdelta agonistinhigh fat diet-induced diabetic mice significantly improved hepatic steatosis and IR. Taken together, we found that hepatic steatosis might not be an essential factor for the development of IR. In contract, PPARdelta plays a critical role in the development of IR in hepatic steatosis status.
In conclusion, we found that activation of PPAR family not only inhibited the inflammatory effects, but also increased insulin sensitivity. Therefore, investigation of PPAR agonists might be an important strategy for diabetes therapy.

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