Catalano Patrick M, Nizielski Steven E, Shao Jianhua, Preston Larraine, Qiao Liping, Friedman Jacob E
Department of Reproductive Biology, Case Western Reserve University School of Medicine, and MetroHealth Medical Center, Cleveland, Ohio 44106, USA.
Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E522-33. doi: 10.1152/ajpendo.00124.2001.
Gestational diabetes mellitus (GDM) is associated with elevated postprandial free fatty acids (FFA) and insulin resistance; however, little is known about the cellular mechanisms underlying insulin resistance to suppress lipolysis during gestation. We evaluated the longitudinal changes in insulin suppression of FFA before pregnancy and in early (12-14 wk) and late (34-36 wk) gestation in obese subjects with normal glucose tolerance and in obese GDM subjects. Abdominal subcutaneous adipose tissue biopsies were also obtained during cesarean delivery from normal obese pregnant (Preg-Con), GDM, and nonpregnant obese control (Non-Preg-Con) subjects during gynecological surgery. GDM subjects had higher basal plasma FFA before pregnancy (P = 0.055). Insulin's ability to suppress FFA levels declined from early to late gestation in both GDM and Preg-Con subjects and was significantly less in GDM subjects compared with Preg-Con subjects over time (P = 0.025). Adipose tissue insulin receptor substrate (IRS)-1 protein levels were 43% lower (P = 0.02) and p85alpha subunit of phosphatidylinositol 3-kinase was twofold higher (P = 0.03) in GDM compared with Preg-Con subjects. The levels of peroxisome proliferator-activated receptor-gamma (PPARgamma) mRNA and protein were lower by 38% in Preg-Con (P = 0.006) and by 48% in GDM subjects (P = 0.005) compared with Non-Preg controls. Lipoprotein lipase and fatty acid-binding protein-2 mRNA levels were 73 and 52% lower in GDM compared with Preg-Con subjects (P < 0.002). Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. Decreased PPARgamma and its target genes may be part of the molecular mechanism to accelerate fat catabolism to meet fetal nutrient demand in late gestation.
妊娠期糖尿病（GDM）与餐后游离脂肪酸（FFA）升高及胰岛素抵抗相关；然而，关于妊娠期间胰岛素抵抗抑制脂肪分解的细胞机制知之甚少。我们评估了糖耐量正常的肥胖受试者和肥胖GDM受试者在孕前、妊娠早期（12 - 14周）和晚期（34 - 36周）胰岛素对FFA抑制作用的纵向变化。在剖宫产时，还从正常肥胖孕妇（Preg-Con）、GDM患者以及妇科手术期间的非妊娠肥胖对照（Non-Preg-Con）受试者获取腹部皮下脂肪组织活检样本。GDM受试者孕前基础血浆FFA水平较高（P = 0.055）。在GDM和Preg-Con受试者中，胰岛素抑制FFA水平的能力从妊娠早期到晚期均下降，且随着时间推移，GDM受试者与Preg-Con受试者相比显著降低（P = 0.025）。与Preg-Con受试者相比，GDM受试者脂肪组织胰岛素受体底物（IRS）-1蛋白水平降低43%（P = 0.02），磷脂酰肌醇3激酶的p85α亚基升高两倍（P = 0.03）。与非妊娠对照相比，Preg-Con受试者中过氧化物酶体增殖物激活受体γ（PPARγ）mRNA和蛋白水平降低38%（P = 0.006），GDM受试者中降低48%（P = 0.005）。与Preg-Con受试者相比，GDM受试者中脂蛋白脂肪酶和脂肪酸结合蛋白-2 mRNA水平分别降低73%和52%（P < 0.002）。因此，GDM女性IRS-1减少，这可能导致随着妊娠进展胰岛素对脂肪分解的抑制作用减弱。PPARγ及其靶基因减少可能是妊娠晚期加速脂肪分解以满足胎儿营养需求的分子机制的一部分。
