Petersen Kitt Falk, Dufour Sylvie, Savage David B, Bilz Stefan, Solomon Gina, Yonemitsu Shin, Cline Gary W, Befroy Douglas, Zemany Laura, Kahn Barbara B, Papademetris Xenophon, Rothman Douglas L, Shulman Gerald I
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12587-94. doi: 10.1073/pnas.0705408104. Epub 2007 Jul 18.
We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approximately 20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.
骨骼肌中的胰岛素抵抗通过改变餐后能量储存的分配模式，促进与代谢综合征相关的致动脉粥样硬化性血脂异常的发展。在摄入两份高碳水化合物混合餐之后，与年龄、体重、体重指数、活动量相匹配的胰岛素敏感对照受试者组成的相似队列相比，年轻、体型瘦且有胰岛素抵抗的受试者的肌肉糖原净合成减少了约60%。相反，胰岛素抵抗受试者的肝脏从头脂肪生成和肝脏甘油三酯合成均增加了2倍以上。这些变化与血浆甘油三酯浓度增加60%以及血浆高密度脂蛋白浓度降低约20%相关，但血浆肿瘤坏死因子-α、白细胞介素-6、脂联素、抵抗素、视黄醇结合蛋白-4的浓度或腹内脂肪量没有差异。这些数据表明，由于肌肉糖原合成减少导致的骨骼肌胰岛素抵抗，可通过将摄入的碳水化合物从骨骼肌糖原合成转变为肝脏从头脂肪生成，从而促进致动脉粥样硬化性血脂异常，导致血浆甘油三酯浓度升高和血浆高密度脂蛋白浓度降低。此外，这些受试者的胰岛素抵抗与血浆肿瘤坏死因子-α、白细胞介素-6、高分子量脂联素、抵抗素、视黄醇结合蛋白-4的浓度变化或腹内肥胖无关，这表明这些因素在代谢综合征早期引起胰岛素抵抗方面不发挥主要作用。
