Boyle Kristen E, Hwang Hyonson, Janssen Rachel C, DeVente James M, Barbour Linda A, Hernandez Teri L, Mandarino Lawrence J, Lappas Martha, Friedman Jacob E
Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2014 Sep 12;9(9):e106872. doi: 10.1371/journal.pone.0106872. eCollection 2014.
The rising prevalence of gestational diabetes mellitus (GDM) affects up to 18% of pregnant women with immediate and long-term metabolic consequences for both mother and infant. Abnormal glucose uptake and lipid oxidation are hallmark features of GDM prompting us to use an exploratory proteomics approach to investigate the cellular mechanisms underlying differences in skeletal muscle metabolism between obese pregnant women with GDM (OGDM) and obese pregnant women with normal glucose tolerance (ONGT). Functional validation was performed in a second cohort of obese OGDM and ONGT pregnant women. Quantitative proteomic analysis in rectus abdominus skeletal muscle tissue collected at delivery revealed reduced protein content of mitochondrial complex I (C-I) subunits (NDUFS3, NDUFV2) and altered content of proteins involved in calcium homeostasis/signaling (calcineurin A, α1-syntrophin, annexin A4) in OGDM (n = 6) vs. ONGT (n = 6). Follow-up analyses showed reduced enzymatic activity of mitochondrial complexes C-I, C-III, and C-IV (-60-75%) in the OGDM (n = 8) compared with ONGT (n = 10) subjects, though no differences were observed for mitochondrial complex protein content. Upstream regulators of mitochondrial biogenesis and oxidative phosphorylation were not different between groups. However, AMPK phosphorylation was dramatically reduced by 75% in the OGDM women. These data suggest that GDM is associated with reduced skeletal muscle oxidative phosphorylation and disordered calcium homeostasis. These relationships deserve further attention as they may represent novel risk factors for development of GDM and may have implications on the effectiveness of physical activity interventions on both treatment strategies for GDM and for prevention of type 2 diabetes postpartum.
妊娠期糖尿病（GDM）患病率的上升影响了多达18%的孕妇，对母亲和婴儿都有直接和长期的代谢后果。葡萄糖摄取异常和脂质氧化是GDM的标志性特征，促使我们采用探索性蛋白质组学方法来研究患有GDM的肥胖孕妇（OGDM）和葡萄糖耐量正常的肥胖孕妇（ONGT）之间骨骼肌代谢差异的细胞机制。在另一组肥胖的OGDM和ONGT孕妇中进行了功能验证。对分娩时收集的腹直肌骨骼肌组织进行定量蛋白质组分析，结果显示，与ONGT组（n = 6）相比，OGDM组（n = 6）中线粒体复合物I（C-I）亚基（NDUFS3、NDUFV2）的蛋白质含量降低，参与钙稳态/信号传导的蛋白质（钙调神经磷酸酶A、α1-肌营养不良素、膜联蛋白A4）含量改变。后续分析表明，与ONGT组（n = 10）相比，OGDM组（n = 8）中线粒体复合物C-I、C-III和C-IV的酶活性降低了60%-75%，尽管线粒体复合物蛋白质含量未观察到差异。两组之间线粒体生物发生和氧化磷酸化的上游调节因子没有差异。然而，OGDM女性的AMPK磷酸化显著降低了75%。这些数据表明，GDM与骨骼肌氧化磷酸化降低和钙稳态紊乱有关。这些关系值得进一步关注，因为它们可能代表GDM发生的新风险因素，并且可能对GDM治疗策略和产后2型糖尿病预防的体育活动干预效果产生影响。
