Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands.
Department of Internal Medicine, Yale School of Medicine, New Haven, CT.
Diabetes Care. 2021 Feb;44(2):489-498. doi: 10.2337/dc20-1644. Epub 2020 Dec 8.
Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans.
We recruited obese subjects who met criteria for bariatric surgery with ( = 16) or without ( = 15) NAFLD and assessed ) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-H]glucose, ) fasting and carbohydrate-driven hepatic DNL using deuterated water (HO), and ) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery.
Compared with subjects without NAFLD, those with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated-not increased-glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: Signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor was increased in subjects with NAFLD.
Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.
2 型糖尿病和非酒精性脂肪性肝病（NAFLD）患者的葡萄糖和甘油三酯生成均增加。数十年来，解释这些矛盾观察结果的主要假说一直是选择性肝胰岛素抵抗，其中胰岛素驱动从头脂肪生成（DNL），而未能抑制葡萄糖生成。在这里，我们旨在在人类中检验这一假说。
我们招募了符合减肥手术标准的肥胖患者，其中伴有（=16）或不伴有（=15）NAFLD，并使用[6,6-H]葡萄糖进行高胰岛素-正常血糖钳夹，评估）胰岛素对肝和外周葡萄糖代谢的调节作用，）使用氘水（HO）评估空腹和碳水化合物驱动的肝 DNL，以及）在减肥手术期间收集的肝活检样本中肝细胞胰岛素信号。
与无 NAFLD 的受试者相比，有 NAFLD 的受试者表现出葡萄糖生成的胰岛素介导抑制受损，并且葡萄糖刺激/高胰岛素脂生成减弱而非增加。果糖刺激/低胰岛素脂生成完整。首次在人类中评估的肝细胞胰岛素信号表现出胰岛素抵抗受试者的近端阻滞：信号从胰岛素受体水平通过葡萄糖和脂生成途径减弱。碳水化合物调节的脂生成转录因子在有 NAFLD 的受试者中增加。
在伴有 NAFLD 的人类中，急性脂生成增加不能通过脂生成胰岛素作用的反常增加来解释脂生成的分子调节改变；相反，脂生成底物可用性的增加可能是关键。
