Samuel Varman T, Shulman Gerald I
J Clin Invest. 2016 Jan;126(1):12-22. doi: 10.1172/JCI77812. Epub 2016 Jan 4.
Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.
当进化为最大化高效能量利用的营养储存途径长期处于能量过剩状态时，就会出现胰岛素抵抗。肝脏和骨骼肌中的异位脂质积累会触发损害胰岛素信号传导的途径，导致肌肉葡萄糖摄取减少和肝糖原合成降低。由于异位脂质导致的肌肉胰岛素抵抗先于肝脏胰岛素抵抗出现，并将摄入的葡萄糖转移至肝脏，导致肝脏从头脂肪生成增加和高脂血症。随后巨噬细胞浸润至白色脂肪组织（WAT）会导致脂肪分解增加，由于脂肪酸酯化增加，这会进一步增加肝脏甘油三酯合成和高脂血症。巨噬细胞诱导的WAT脂肪分解还会刺激肝脏糖异生，通过增加脂肪酸向肝脏的输送促进空腹和餐后高血糖，这会导致肝脏乙酰辅酶A含量增加，丙酮酸羧化酶的强效激活剂，以及甘油转化为葡萄糖增加。这些底物调节过程大多独立于肝脏中的胰岛素信号传导，但依赖于WAT中的胰岛素信号传导，而WAT中的胰岛素信号传导会因炎症而出现缺陷。减少异位脂质储存并减少巨噬细胞诱导的WAT脂肪分解的疗法将逆转2型糖尿病的根本原因。
