Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
Liver Int. 2016 Nov;36(11):1563-1579. doi: 10.1111/liv.13185. Epub 2016 Jun 30.
Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi-directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes. Indeed, at the molecular level, hepatic lipogenesis and hepatic glucose production depend on differentially regulated branches of the insulin signalling pathway. Furthermore, genetic studies suggest that excess hepatic fat is associated with progressive liver disease, but does not always increase the risk of incident type 2 diabetes. Here, we will briefly review the epidemiological, pathophysiological and molecular evidence linking NAFLD to the development of type 2 diabetes. We will also discuss some recent genetic and therapeutic advances that seem to challenge a causal role of NAFLD in the pathogenesis type 2 diabetes, and propose a working hypothesis to explain this apparent conundrum. In conclusion, progressive liver disease and type 2 diabetes are divergent though inter-related consequences of insulin resistance and the metabolic syndrome.
越来越多的流行病学证据表明，非酒精性脂肪性肝病（NAFLD）是 2 型糖尿病和代谢综合征其他特征发展的早期预测因子和决定因素。这一发现可能对 2 型糖尿病及其慢性并发症的诊断、预防和治疗具有重要的临床意义。然而，鉴于 NAFLD、胰岛素抵抗和慢性高血糖之间的复杂和双向关系，要区分 NAFLD 是胰岛素抵抗和 2 型糖尿病的原因还是结果极其困难。事实上，在分子水平上，肝脂肪生成和肝葡萄糖生成依赖于胰岛素信号通路的不同调节分支。此外，遗传研究表明，肝脏脂肪过多与进行性肝病有关，但并不总是增加 2 型糖尿病发病的风险。在这里，我们将简要回顾将 NAFLD 与 2 型糖尿病的发展联系起来的流行病学、病理生理学和分子证据。我们还将讨论一些最近的遗传和治疗进展，这些进展似乎对 NAFLD 在 2 型糖尿病发病机制中的因果作用提出了挑战，并提出了一个工作假说来解释这一明显的难题。总之，进行性肝病和 2 型糖尿病是胰岛素抵抗和代谢综合征的不同但相互关联的后果。
