根據衛福部2020年統計,糖尿病為國人10大死因第五名,且糖尿病患者也在逐年增加。骨骼肌為人體主要的代謝器官之一,進食後受到胰島素刺激,負責攝入大部分的葡萄糖藉此調控血液中葡萄糖的濃度,而骨骼肌的胰島素阻抗被認為是高血糖發生的前兆之一。胎兒規劃指的是胎兒在母體內發育的關鍵時期,受子宮環境刺激而影響子代日後的健康,已知不良的子宮環境可能透過表觀遺傳調控造成子代的代謝失調。在實驗室先前的研究中,發現患有高膽固醇血症之孕鼠所產下的雄性子代,在胰島素耐受性試驗結果中有較差的胰島素敏感性,且在給予孕鼠DNA甲基轉移酶抑制劑5-aza-2'-deoxycytidine (5-Aza-dC)後得到改善。本實驗沿用實驗室建立的模式,以西方飲食誘導ApoE-/-母鼠產生高膽固醇血症,並以給予控制飲食的ApoE-/-母鼠作為飲食的對照組,之後分別將餵食控制飲食與西方飲食的母鼠處理5-Aza-dC抑制其DNA甲基化,另外以給予PBS之母鼠作為對照組,處理四週後進行交配,所產下的子代離乳後一律給予西方飲食餵養,發現給予5-Aza-dC的母鼠所產下的雄性子代血球有較低的DNA甲基化程度,另外,餵食西方飲食的母鼠所產下的雄性子代胰島素敏感性與葡萄糖耐受性降低,在肌肉中也觀察到一些不利於肌肉代謝葡萄糖的表徵,包括:肌肉中的胰島素訊號傳導降低、肌纖維截面積縮小等,在基因的表現上似乎也說明親代母鼠餵食西方飲食會導致子代的骨骼肌生合成相關基因表現量增加,同時使骨骼肌的修復的負調節因子Mstn的基因表現量提升,而在餵食西方飲食的親代母鼠施打5-Aza-dC後其所產下的雄性子代胰島素敏感性與葡萄糖耐受性獲得改善,基因表現的部分則發現肌肉的受損似乎有減緩且骨骼肌修復的負調節因子Mstn的基因表現量降低,說明親代母鼠施打甲基轉移酶抑制劑,可能部分改善子代肌肉的醣代謝能力,使子代全身性的胰島素敏感性與葡萄糖耐受性獲得改善。
Skeletal muscle is the primary site for glucose uptake and storage. Insulin resistance in skeletal muscle is a key feature of pre-diabetic state and may lead to hyperglycemia. Fetal programming is a concept that suggests certain events occurring during critical points of pregnancy may have an impact on long-term offspring health, which might be mediated through epigenetic modification. This study was to test the hypothesis that maternal DNA methyltransferase (DNMT) inhibitor treatment before pregnancy and during lactation would produce offspring with a more favorable glucose homeostasis than offspring from untreated dams. Female apolipoprotein (Apo) E-deficient mice were fed a control diet (CD) or a high fat/high cholesterol Western-type diet (WD) before and throughout pregnancy and lactation. DNMT inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) or PBS was given to females before pregnancy and during lactation, and their offspring were weaned onto a WD postnatally. Both 5-Aza-dC-treated dams and their offspring demonstrated lower DNA methylation levels in the blood. While maternal WD treatment impaired glucose tolerance and insulin sensitivity in male offspring, which might correlate with higher Mstn expression and higher content of glycolytic muscle fiber, however, maternal 5-Aza-dC treatment could partially reverse the phenotype. In addition, offspring from maternal 5-Aza-dC-treated dams showed improved forelimb strength and larger muscle cross-section area compared with offspring from PBS-treated dams. In summary, maternal 5-Aza-dC treatment is correlated with lower Mstn expression in male offspring, which may protect offspring muscle against systemic metabolic deterioration, to improves whole body glucose homeostasis in male offspring.