Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA.
Diabetes Research and Training Center, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA.
Nat Metab. 2023 Jul;5(7):1101-1110. doi: 10.1038/s42255-023-00843-6. Epub 2023 Jul 17.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly prevalent fellow traveller with the insulin resistance that underlies type 2 diabetes mellitus. However, the mechanistic connection between MAFLD and impaired insulin action remains unclear. In this Perspective, we review data from humans to elucidate insulin's aetiological role in MAFLD. We focus particularly on the relative preservation of insulin's stimulation of triglyceride (TG) biosynthesis despite its waning ability to curb hepatic glucose production (HGP). To explain this apparent 'selective insulin resistance', we propose that hepatocellular processes that lead to TG accumulation require less insulin signal transduction, or 'insulinization,' than do those that regulate HGP. As such, mounting hyperinsulinaemia that barely compensates for aberrant HGP in insulin-resistant states more than suffices to maintain hepatic TG biosynthesis. Thus, even modestly elevated or context-inappropriate insulin levels, when sustained day and night within a heavily pro-lipogenic metabolic milieu, may translate into substantial cumulative TG biosynthesis in the insulin-resistant state.
代谢相关脂肪性肝病（MAFLD）是 2 型糖尿病（T2DM）胰岛素抵抗的一个日益普遍的伴随疾病。然而，MAFLD 与胰岛素作用受损之间的机制联系尚不清楚。在本观点中，我们回顾了来自人类的研究数据，以阐明胰岛素在 MAFLD 中的病因作用。我们特别关注尽管胰岛素抑制肝葡萄糖生成（HGP）的能力下降，但它对甘油三酯（TG）生物合成的刺激作用仍然存在。为了解释这种明显的“选择性胰岛素抵抗”，我们提出导致 TG 积累的肝细胞过程需要较少的胰岛素信号转导，或者说“胰岛素化”，而不是调节 HGP 的过程。因此，在胰岛素抵抗状态下，即使是勉强代偿异常 HGP 的高胰岛素血症，也足以维持肝 TG 生物合成。因此，即使是适度升高或与环境不适当的胰岛素水平，如果在富含促脂生成的代谢环境中持续存在于白天和黑夜，也可能在胰岛素抵抗状态下转化为大量累积的 TG 生物合成。
